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1.
Biochem Biophys Res Commun ; 718: 150037, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38735135

RESUMEN

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80 % of lung cancer (LC) cases, making it the primary cause of cancer-related mortality worldwide. T-box transcription factor 5 (TBX5) is an important regulator of embryonic and organ development and plays a key role in cancer development. Here, our objective was to investigate the involvement of TBX5 in ferroptosis within LC cells and the underlying mechanisms. METHODS: First, TBX5 expression was examined in human LC cells. Next, overexpression of TBX5 and Yes1-associated transcriptional regulator (YAP1) and knockdown of TEA domain 1 (TEAD1) were performed in A549 and NCI-H1703 cells. The proliferation ability of A549 and NCI-H1703 cells, GSH, MDA, ROS, and Fe2+ levels were measured. Co-immunoprecipitation (Co-IP) was performed to verify whether TBX5 protein could bind YAP1. Then TBX5, YAP1, TEAD1, GPX4, p53, FTH1, SLC7A11 and PTGS2 protein levels were assessed. Finally, we verified the effect of TBX5 on ferroptosis in LC cells in vivo. RESULTS: TBX5 expression was down-regulated in LC cells, especially in A549 and NCI-H1703 cells. Overexpression of TBX5 significantly decreased proliferation ability of A549 and NCI-H1703 cells, downregulated GPX4 and GSH levels, and upregulated MDA, ROS, and Fe2+ levels. Co-IP verified that TBX5 protein could bind YAP1. Moreover, oe-YAP1 promoted proliferation ability of A549 and NCI-H1703 cells transfected with Lv-TBX5, upregulated GPX4 and GSH levels and downregulated MDA, ROS, and Fe2+ levels. Additionally, oe-YAP1 promoted FTH1 and SLC7A11 levels and inhibited p53 and PTGS2 levels in A549 and NCI-H1703 cells transfected with Lv-TBX5. However, transfection with si-TEAD1 further reversed these effects. In vivo experiments further validated that TBX5 promoted ferroptosis in LC cells. CONCLUSIONS: TBX5 inhibited the activation of YAP1-TEAD1 pathway to promote ferroptosis in LC cells.


Asunto(s)
Ferroptosis , Neoplasias Pulmonares , Proteínas de Dominio T Box , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Proteínas Señalizadoras YAP , Ferroptosis/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción de Dominio TEA/metabolismo , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Animales , Línea Celular Tumoral , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones Desnudos , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones , Regulación Neoplásica de la Expresión Génica , Células A549 , Transducción de Señal , Especies Reactivas de Oxígeno/metabolismo
2.
Cell Biol Toxicol ; 40(1): 30, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740637

RESUMEN

In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.


Asunto(s)
Carcinoma Ductal Pancreático , Movimiento Celular , Proliferación Celular , Proteínas de Unión al ADN , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia , MicroARNs , Neoplasias Pancreáticas , ARN Largo no Codificante , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción de Dominio TEA/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/genética , Movimiento Celular/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Animales , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Transducción de Señal/genética , Ratones Desnudos , Ratones
3.
Cell Metab ; 36(5): 1030-1043.e7, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38670107

RESUMEN

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.


Asunto(s)
Proteínas de Unión al ADN , Cirrosis Hepática , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Factores de Transcripción de Dominio TEA/metabolismo , Animales , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Humanos , Ratones , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Empalme Alternativo , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Células Estrelladas Hepáticas/metabolismo , Masculino , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , Ratones Noqueados
4.
FEBS Lett ; 598(9): 1045-1060, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38594215

RESUMEN

TEAD transcription factors play a central role in the Hippo signaling pathway. In this study, we focused on transcriptional enhancer factor TEF-3 (TEAD4), exploring its regulation by the deubiquitinase OTU domain-containing protein 6A (OTUD6A). We identified OTUD6A as a TEAD4-interacting deubiquitinase, positively influencing TEAD-driven transcription without altering TEAD4 stability. Structural analyses revealed specific interaction domains: the N-terminal domain of OTUD6A and the YAP-binding domain of TEAD4. Functional assays demonstrated the positive impact of OTUD6A on the transcription of YAP-TEAD target genes. Despite no impact on TEAD4 nuclear localization, OTUD6A selectively modulated nuclear interactions, enhancing YAP-TEAD4 complex formation while suppressing VGLL4 (transcription cofactor vestigial-like protein 4)-TEAD4 interaction. Critically, OTUD6A facilitated YAP-TEAD4 complex binding to target gene promoters. Our study unveils the regulatory landscape of OTUD6A on TEAD4, providing insights into diseases regulated by YAP-TEAD complexes.


Asunto(s)
Proteínas de Unión al ADN , Proteínas Musculares , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Factores de Transcripción de Dominio TEA/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Humanos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/química , Células HEK293 , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/química , Transcripción Genética , Unión Proteica , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Regiones Promotoras Genéticas
5.
Commun Biol ; 7(1): 497, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658677

RESUMEN

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.


Asunto(s)
Acrilamidas , Resistencia a Antineoplásicos , Receptores ErbB , Indoles , Neoplasias Pulmonares , Mutación , Pirimidinas , Factores de Transcripción , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Resistencia a Antineoplásicos/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Gefitinib/farmacología , Vía de Señalización Hippo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transducción de Señal , Factores de Transcripción de Dominio TEA , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/farmacología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Sistemas CRISPR-Cas
6.
Dev Cell ; 59(9): 1146-1158.e6, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38574734

RESUMEN

Transcription factors (TFs) play important roles in early embryonic development, but factors regulating TF action, relationships in signaling cascade, genome-wide localizations, and impacts on cell fate transitions during this process have not been clearly elucidated. In this study, we used uliCUT&RUN-seq to delineate a TFAP2C-centered regulatory network, showing that it involves promoter-enhancer interactions and regulates TEAD4 and KLF5 function to mediate cell polarization. Notably, we found that maternal retinoic acid metabolism regulates TFAP2C expression and function by inducing the active demethylation of SINEs, indicating that the RARG-TFAP2C-TEAD4/KLF5 axis connects the maternal-to-zygotic transition to polarization. Moreover, we found that both genomic imprinting and SNP-transferred genetic information can influence TF positioning to regulate parental gene expressions in a sophisticated manner. In summary, we propose a ternary model of TF regulation in murine embryonic development with TFAP2C as the core element and metabolic, epigenetic, and genetic information as nodes connecting the pathways.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Factor de Transcripción AP-2 , Factores de Transcripción , Animales , Factor de Transcripción AP-2/metabolismo , Factor de Transcripción AP-2/genética , Ratones , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Femenino , Implantación del Embrión/genética , Redes Reguladoras de Genes , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Desarrollo Embrionario/genética , Factores de Transcripción de Dominio TEA/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Regiones Promotoras Genéticas/genética , Tretinoina/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/genética
7.
J Phys Chem B ; 128(16): 3795-3806, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38606592

RESUMEN

The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, it translocates into the nucleus, where it associates with TEAD transcription factors. This partnership is instrumental in regulating the transcription of progrowth and antiapoptotic genes. Thus, in many cancers, aberrantly hyperactivated YAP/TAZ promotes oncogenesis by contributing to cancer cell proliferation, metastasis, and therapy resistance. Because YAP and TAZ exert their oncogenic effects by binding with TEAD, it is critical to understand this key interaction to develop cancer therapeutics. Previous research has indicated that TEAD undergoes autopalmitoylation at a conserved cysteine, and small molecules that inhibit TEAD palmitoylation disrupt effective YAP/TAZ binding. However, how exactly palmitoylation contributes to YAP/TAZ-TEAD interactions and how the TEAD palmitoylation inhibitors disrupt this interaction remains unknown. Utilizing molecular dynamics simulations, our investigation not only provides detailed atomistic insight into the YAP/TAZ-TEAD dynamics but also unveils that the inhibitor studied influences the binding of YAP and TAZ to TEAD in distinct manners. This discovery has significant implications for the design and deployment of future molecular interventions targeting this interaction.


Asunto(s)
Lipoilación , Simulación de Dinámica Molecular , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Humanos , Aciltransferasas/metabolismo , Aciltransferasas/antagonistas & inhibidores , Aciltransferasas/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/química , Regulación Alostérica/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/química , Unión Proteica , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Factores de Transcripción de Dominio TEA/química , Factores de Transcripción de Dominio TEA/metabolismo , Transactivadores/metabolismo , Transactivadores/química , Transactivadores/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/química , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/química , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Proteínas Señalizadoras YAP/química , Proteínas Señalizadoras YAP/metabolismo
8.
EMBO J ; 43(10): 1965-1989, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38605224

RESUMEN

The transition of mouse embryonic stem cells (ESCs) between serum/LIF and 2i(MEK and GSK3 kinase inhibitor)/LIF culture conditions serves as a valuable model for exploring the mechanisms underlying ground and confused pluripotent states. Regulatory networks comprising core and ancillary pluripotency factors drive the gene expression programs defining stable naïve pluripotency. In our study, we systematically screened factors essential for ESC pluripotency, identifying TEAD2 as an ancillary factor maintaining ground-state pluripotency in 2i/LIF ESCs and facilitating the transition from serum/LIF to 2i/LIF ESCs. TEAD2 exhibits increased binding to chromatin in 2i/LIF ESCs, targeting active chromatin regions to regulate the expression of 2i-specific genes. In addition, TEAD2 facilitates the expression of 2i-specific genes by mediating enhancer-promoter interactions during the serum/LIF to 2i/LIF transition. Notably, deletion of Tead2 results in reduction of a specific set of enhancer-promoter interactions without significantly affecting binding of chromatin architecture proteins, CCCTC-binding factor (CTCF), and Yin Yang 1 (YY1). In summary, our findings highlight a novel prominent role of TEAD2 in orchestrating higher-order chromatin structures of 2i-specific genes to sustain ground-state pluripotency.


Asunto(s)
Cromatina , Proteínas de Unión al ADN , Células Madre Embrionarias de Ratones , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Animales , Ratones , Factores de Transcripción de Dominio TEA/metabolismo , Cromatina/metabolismo , Cromatina/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias de Ratones/citología , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Regiones Promotoras Genéticas , Elementos de Facilitación Genéticos
9.
Mol Syst Biol ; 20(4): 374-402, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38459198

RESUMEN

Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.


Asunto(s)
Hígado Graso , Enfermedad del Hígado Graso no Alcohólico , Animales , Femenino , Humanos , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Estrógenos , Hígado Graso/genética , Hígado Graso/metabolismo , Expresión Génica , Hígado/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/uso terapéutico , Factores de Transcripción de Dominio TEA
10.
J Biol Chem ; 300(4): 107208, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38521502

RESUMEN

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.


Asunto(s)
Carcinoma Hepatocelular , Proteína 61 Rica en Cisteína , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Factor de Crecimiento Transformador beta , Proteínas Señalizadoras YAP , Animales , Humanos , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular , Proteína 61 Rica en Cisteína/metabolismo , Proteína 61 Rica en Cisteína/genética , Minería de Datos , Regulación Neoplásica de la Expresión Génica/genética , Vía de Señalización Hippo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Ratones Desnudos , Regiones Promotoras Genéticas , Transducción de Señal/genética , Proteína Smad2/metabolismo , Proteína Smad2/genética , Proteína smad3/metabolismo , Proteína smad3/genética , Factores de Transcripción de Dominio TEA/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Regulación hacia Arriba , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética
11.
J Cell Mol Med ; 28(7): e18266, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38501838

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC), a very aggressive tumour, is currently the third leading cause of cancer-related deaths. Unfortunately, many patients face the issue of inoperability at the diagnostic phase leading to a quite dismal prognosis. The onset of metastatic processes has a crucial role in the elevated mortality rates linked to PDAC. Individuals with metastatic advances receive only palliative therapy and have a grim prognosis. It is essential to carefully analyse the intricacies of the metastatic process to enhance the prognosis for individuals with PDAC. Malignancy development is greatly impacted by the process of macrophage efferocytosis. Our current knowledge about the complete range of macrophage efferocytosis activities in PDAC and their intricate interactions with tumour cells is still restricted. This work aims to resolve communication gaps and pinpoint the essential transcription factor that is vital in the immunological response of macrophage populations. We analysed eight PDAC tissue samples sourced from the gene expression omnibus. We utilized several software packages such as Seurat, DoubletFinder, Harmony, Pi, GSVA, CellChat and Monocle from R software together with pySCENIC from Python, to analyse the single-cell RNA sequencing (scRNA-seq) data collected from the PDAC samples. This study involved the analysis of a comprehensive sample of 22,124 cells, which were classified into distinct cell types. These cell types encompassed endothelial and epithelial cells, PDAC cells, as well as various immune cells, including CD4+ T cells, CD8+ T cells, NK cells, B cells, plasma cells, mast cells, monocytes, DC cells and different subtypes of macrophages, namely C0 macrophage TGM2+, C1 macrophage PFN1+, C2 macrophage GAS6+ and C3 macrophage APOC3+. The differentiation between tumour cells and epithelial cells was achieved by the implementation of CopyKat analysis, resulting in the detection and categorization of 1941 PDAC cells. The amplification/deletion patterns observed in PDAC cells on many chromosomes differ significantly from those observed in epithelial cells. The study of Pseudotime Trajectories demonstrated that the C0 macrophage subtype expressing TGM2+ had the lowest level of differentiation. Additionally, the examination of gene set scores related to efferocytosis suggested that this subtype displayed higher activity during the efferocytosis process compared to other subtypes. The most active transcription factors for each macrophage subtype were identified as BACH1, NFE2, TEAD4 and ARID3A. In conclusion, the examination of human PDAC tissue samples using immunofluorescence analysis demonstrated the co-localization of CD68 and CD11b within regions exhibiting the presence of keratin (KRT) and alpha-smooth muscle actin (α-SMA). This observation implies a spatial association between macrophages, fibroblasts, and epithelial cells. There is variation in the expression of efferocytosis-associated genes between C0 macrophage TGM2+ and other macrophage cell types. This observation implies that the diversity of macrophage cells might potentially influence the metastatic advancement of PDAC. Moreover, the central transcription factor of different macrophage subtypes offers a promising opportunity for targeted immunotherapy in the treatment of PDAC.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Eferocitosis , Análisis de Expresión Génica de una Sola Célula , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Macrófagos/metabolismo , Factores de Transcripción/metabolismo , Microambiente Tumoral , Proteínas de Unión al ADN/genética , Factores de Transcripción de Dominio TEA , Profilinas/genética
12.
BMC Med ; 22(1): 57, 2024 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-38317232

RESUMEN

BACKGROUND: Abnormal placental development is a significant factor contributing to perinatal morbidity and mortality, affecting approximately 5-7% of pregnant women. Trophoblast syncytialization plays a pivotal role in the establishment and maturation of the placenta, and its dysregulation is closely associated with several pregnancy-related disorders, including preeclampsia and intrauterine growth restriction. However, the underlying mechanisms and genetic determinants of syncytialization are largely unknown. METHODS: We conducted a systematic drug screen using an epigenetic compound library to systematically investigate the epigenetic mechanism essential for syncytialization, and identified mixed lineage leukemia 1 (MLL1), a histone 3 lysine 4 methyltransferase, as a crucial regulator of trophoblast syncytialization. BeWo cells were utilized to investigate the role of MLL1 during trophoblast syncytialization. RNA sequencing and CUT&Tag were further performed to search for potential target genes and the molecular pathways involved. Human placenta tissue was used to investigate the role of MLL1 in TEA domain transcription factor 4 (TEAD4) expression and the upstream signaling during syncytialization. A mouse model was used to examine whether inhibition of MLL1-mediated H3K4me3 regulated placental TEAD4 expression and fetoplacental growth. RESULTS: Genetic knockdown of MLL1 or pharmacological inhibition of the MLL1 methyltransferase complex (by MI-3454) markedly enhanced syncytialization, while overexpression of MLL1 inhibited forskolin (FSK)-induced syncytiotrophoblast formation. In human placental villous tissue, MLL1 was predominantly localized in the nuclei of cytotrophoblasts. Moreover, a notable upregulation in MLL1 expression was observed in the villus tissue of patients with preeclampsia compared with that in the control group. Based on RNA sequencing and CUT&Tag analyses, depletion of MLL1 inhibited the Hippo signaling pathway by suppressing TEAD4 expression by modulating H3K4me3 levels on the TEAD4 promoter region. TEAD4 overexpression significantly reversed the FSK-induced or MLL1 silencing-mediated trophoblast syncytialization. Additionally, decreased hypoxia-inducible factor 1A (HIF1A) enrichment at the MLL1 promoter was observed during syncytialization. Under hypoxic conditions, HIF1A could bind to and upregulate MLL1, leading to the activation of the MLL1/TEAD4 axis. In vivo studies demonstrated that the administration of MI-3454 significantly enhanced fetal vessel development and increased the thickness of the syncytial layer, thereby supporting fetoplacental growth. CONCLUSIONS: These results revealed a novel epigenetic mechanism underlying the progression of syncytialization with MLL1, and suggest potential avenues for identifying new therapeutic targets for pregnancy-related disorders.


Asunto(s)
N-Metiltransferasa de Histona-Lisina , Proteína de la Leucemia Mieloide-Linfoide , Placenta , Preeclampsia , Animales , Femenino , Humanos , Ratones , Embarazo , Epigénesis Genética , Placenta/metabolismo , Factores de Transcripción de Dominio TEA , Trofoblastos/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo
13.
Biochim Biophys Acta Gen Subj ; 1868(5): 130592, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38395204

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) cell-intrinsic programmed death 1 (PD-1) promotes tumor progression. However, the mechanisms that regulate its expression are unclear. This study investigated the impact of alpha-fetoprotein (AFP) on HCC cell-intrinsic PD-1 expression. METHODS: The expression of PD-1 and AFP at the gene and protein levels was detected using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). Proteins interacting with AFP were examined by co-immunoprecipitation (CO-IP). Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were used to identify transcription-enhanced association domain 1 (TEAD1) binding to the promoter of PD-1. RESULTS: The expression of HCC cell-intrinsic PD-1 was positively correlated with AFP. Mechanistically, AFP inhibited the phosphorylation of large tumor suppressor 2 (LATS2) and yes-associated protein (YAP). As a result, YAP is transferred to the nucleus and forms a transcriptional complex with TEAD1, promoting PD-1 transcription by binding to its promoter. CONCLUSION: AFP is an upstream regulator of the HCC cell-intrinsic PD-1 and increases PD-1 expression via the LATS2/YAP/TEAD1 axis. GENERAL: Our findings provide insight into the mechanisms of HCC development and offer new ideas for further in-depth studies of HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , alfa-Fetoproteínas/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Factores de Transcripción de Dominio TEA
14.
Signal Transduct Target Ther ; 9(1): 45, 2024 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-38374140

RESUMEN

Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq and ChIP-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.


Asunto(s)
Factores de Transcripción de Dominio TEA , Factores de Transcripción , Remodelación Ventricular , Animales , Ratones , Miofibroblastos/metabolismo , Miofibroblastos/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción de Dominio TEA/genética , Factores de Transcripción de Dominio TEA/metabolismo , Factores de Transcripción/genética , Remodelación Ventricular/genética , Proteína Wnt4/metabolismo , Fibroblastos/metabolismo , Proteínas que Contienen Bromodominio/metabolismo
15.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38396900

RESUMEN

TEAD4 is a transcription factor that plays a crucial role in the Hippo pathway by regulating the expression of genes related to proliferation and apoptosis. It is also involved in the maintenance and differentiation of the trophectoderm during pre- and post-implantation embryonic development. An alternative promoter for the TEAD4 gene was identified through epigenetic profile analysis, and a new transcript from the intronic region of TEAD4 was discovered using the 5'RACE method. The transcript of the novel promoter encodes a TEAD4 isoform (TEAD4-ΔN) that lacks the DNA-binding domain but retains the C-terminal protein-protein interaction domain. Gene expression studies, including end-point PCR and Western blotting, showed that full-length TEAD4 was present in all investigated tissues. However, TEAD4-ΔN was only detectable in certain cell types. The TEAD4-ΔN promoter is conserved throughout evolution and demonstrates transcriptional activity in transient-expression experiments. Our study reveals that TEAD4 interacts with the alternative promoter and increases the expression of the truncated isoform. DNA methylation plays a crucial function in the restricted expression of the TEAD4-ΔN isoform in specific tissues, including the umbilical cord and the placenta. The data presented indicate that the DNA-methylation status of the TEAD4-ΔN promoter plays a critical role in regulating organ size, cancer development, and placenta differentiation.


Asunto(s)
Proteínas de Unión al ADN , Regiones Promotoras Genéticas , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Femenino , Humanos , Embarazo , ADN , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Factores de Transcripción de Dominio TEA/genética , Factores de Transcripción/metabolismo
16.
Nat Commun ; 15(1): 583, 2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38233381

RESUMEN

In contrast to rodents, the mechanisms underlying human trophectoderm and early placenta specification are understudied due to ethical barriers and the scarcity of embryos. Recent reports have shown that human pluripotent stem cells (PSCs) can differentiate into trophectoderm (TE)-like cells (TELCs) and trophoblast stem cells (TSCs), offering a valuable in vitro model to study early placenta specification. Here, we demonstrate that the VGLL1 (vestigial-like family member 1), which is highly expressed during human and non-human primate TE specification in vivo but is negligibly expressed in mouse, is a critical regulator of cell fate determination and self-renewal in human TELCs and TSCs derived from naïve PSCs. Mechanistically, VGLL1 partners with the transcription factor TEAD4 (TEA domain transcription factor 4) to regulate chromatin accessibility at target gene loci through histone acetylation and acts in cooperation with GATA3 and TFAP2C. Our work is relevant to understand primate early embryogenesis and how it differs from other mammalian species.


Asunto(s)
Células Madre Pluripotentes , Factores de Transcripción , Embarazo , Femenino , Humanos , Ratones , Animales , Linaje de la Célula/genética , Factores de Transcripción/genética , Trofoblastos/fisiología , Diferenciación Celular/genética , Mamíferos , Primates , Proteínas de Unión al ADN/genética , Factores de Transcripción de Dominio TEA
17.
Proc Natl Acad Sci U S A ; 121(6): e2304619121, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38289962

RESUMEN

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.


Asunto(s)
Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Oxaliplatino/farmacología , Terapia Neoadyuvante/métodos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromatina , Resultado del Tratamiento , Factores de Transcripción de Dominio TEA , Ubiquitina-Proteína Ligasas , Proteínas de Unión a Retinoblastoma
18.
Adv Sci (Weinh) ; 11(11): e2305547, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38169150

RESUMEN

The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGFß1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of α1- and α2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of α1- and α2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFß1-driven EMT.


Asunto(s)
Próstata , Neoplasias de la Próstata , Masculino , Humanos , Próstata/metabolismo , Próstata/patología , Línea Celular Tumoral , Neoplasias de la Próstata/genética , Transducción de Señal/genética , Integrina alfa2/genética , Integrina alfa2/metabolismo , Factores de Transcripción de Dominio TEA
19.
Adv Sci (Weinh) ; 11(12): e2305677, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38225750

RESUMEN

Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.


Asunto(s)
Insuficiencia Cardíaca , Sumoilación , Humanos , Ratones , Animales , Cardiomegalia , Factores de Transcripción/metabolismo , Insuficiencia Cardíaca/metabolismo , Regulación de la Expresión Génica , Factores de Transcripción de Dominio TEA
20.
Biochim Biophys Acta Rev Cancer ; 1879(1): 189050, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38072284

RESUMEN

Cancer metastasis is a complex process influenced by various factors, including epithelial-mesenchymal transition (EMT), tumor cell proliferation, tumor microenvironment, and cellular metabolic status, which remains a significant challenge in clinical oncology, accounting for a majority of cancer-related deaths. TEAD4, a key mediator of the Hippo signaling pathway, has been implicated in regulating these factors that are all critical in the metastatic cascade. TEAD4 drives tumor metastasis and chemoresistance, and its upregulation is associated with poor prognosis in many types of cancers, making it an attractive target for therapeutic intervention. TEAD4 promotes EMT by interacting with coactivators and activating the transcription of genes involved in mesenchymal cell characteristics and extracellular matrix remodeling. Additionally, TEAD4 enhances the stemness of cancer stem cells (CSCs) by regulating the expression of genes associated with CSC maintenance. TEAD4 contributes to metastasis by modulating the secretion of paracrine factors and promoting heterotypic cellular communication. In this paper, we highlight the central role of TEAD4 in cancer metastasis and chemoresistance and its impact on various aspects of tumor biology. Understanding the mechanistic basis of TEAD4-mediated processes can facilitate the development of targeted therapies and combination approaches to combat cancer metastasis and improve treatment outcomes.


Asunto(s)
Resistencia a Antineoplásicos , Neoplasias , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Transición Epitelial-Mesenquimal/fisiología , Microambiente Tumoral , Factores de Transcripción de Dominio TEA
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