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1.
Proc Natl Acad Sci U S A ; 121(28): e2405100121, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38950372

RESUMEN

N6-methyladenosine (m6A) is a fundamentally important RNA modification for gene regulation, whose function is achieved through m6A readers. However, whether and how m6A readers play regulatory roles during fruit ripening and quality formation remains unclear. Here, we characterized SlYTH2 as a tomato m6A reader protein and profiled the binding sites of SlYTH2 at the transcriptome-wide level. SlYTH2 undergoes liquid-liquid phase separation and promotes RNA-protein condensate formation. The target mRNAs of SlYTH2, namely m6A-modified SlHPL and SlCCD1B associated with volatile synthesis, are enriched in SlYTH2-induced condensates. Through polysome profiling assays and proteomic analysis, we demonstrate that knockout of SlYTH2 expedites the translation process of SlHPL and SlCCD1B, resulting in augmented production of aroma-associated volatiles. This aroma enrichment significantly increased consumer preferences for CRISPR-edited fruit over wild type. These findings shed light on the underlying mechanisms of m6A in plant RNA metabolism and provided a promising strategy to generate fruits that are more attractive to consumers.


Asunto(s)
Adenosina , Frutas , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas , Biosíntesis de Proteínas , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Solanum lycopersicum/crecimiento & desarrollo , Frutas/metabolismo , Frutas/genética , Adenosina/metabolismo , Adenosina/análogos & derivados , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Odorantes/análisis
2.
Int J Mol Sci ; 25(11)2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38891773

RESUMEN

Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells.


Asunto(s)
Anoicis , Proteínas de Ciclo Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular , Sirtuinas , Humanos , Anoicis/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Sirtuinas/metabolismo , Sirtuinas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Regulación hacia Abajo , Transducción de Señal , Epigénesis Genética
3.
Diabetes ; 72(8): 1083-1094, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37224383

RESUMEN

The induction of beige adipocytes in white adipose tissue (WAT), also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of the Mettl3 gene undermines WAT beiging and impairs the metabolic capability of mice fed with a high-fat diet. Mechanistically, METTL3-catalyzed m6A installation on thermogenic mRNAs, including Krüppel-like factor 9 (Klf9), prevents their degradation. Activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate promotes WAT beiging, reduces body weight, and corrects metabolic disorders in diet-induced obese mice. These findings uncover a novel epitranscriptional mechanism in WAT beiging and identify METTL3 as a potential therapeutic target for obesity-associated diseases. ARTICLE HIGHLIGHTS: METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging. Depletion of Mettl3 undermines WAT beiging and impairs thermogenesis. METTL3-mediated m6A installation promotes the stability of Krüppel-like factor 9 (Klf9). KLF9 rescues impaired beiging elicited by Mettl3 depletion. Pharmaceutical activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate induces WAT beiging. Methyl piperidine-3-carboxylate corrects obesity-associated disorders. The METTL3-KLF9 pathway may serve as a potential therapeutic target for obesity-associated diseases.


Asunto(s)
Tejido Adiposo Blanco , Obesidad , Animales , Ratones , Tejido Adiposo Blanco/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Ligandos , Metiltransferasas/genética , Metiltransferasas/metabolismo , Obesidad/genética , Obesidad/metabolismo , Piperidinas , ARN Mensajero/genética , ARN Mensajero/metabolismo
4.
Nat Commun ; 14(1): 1379, 2023 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-36914671

RESUMEN

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. N(6)-methyladenosine (m6A) RNA modification has been recently identified as a key regulator of obesity, while the detailed mechanism is elusive. Here, we find that YTH RNA binding protein 1 (YTHDF1), an m6A reader, acts as an essential regulator of white adipose tissue metabolism. The expression of YTHDF1 decreases in adipose tissue of male mice fed a high-fat diet. Adipocyte-specific Ythdf1 deficiency exacerbates obesity-induced metabolic defects and inhibits beiging of inguinal white adipose tissue (iWAT) in male mice. By contrast, male mice with WAT-specific YTHDF1 overexpression are resistant to obesity and shows promotion of beiging. Mechanistically, YTHDF1 regulates the translation of diverse m6A-modified mRNAs. In particular, YTHDF1 facilitates the translation of bone morphogenetic protein 8b (Bmp8b) in an m6A-dependent manner to induce the beiging process. Here, we show that YTHDF1 may be an potential therapeutic target for the management of obesity-associated diseases.


Asunto(s)
Adipocitos , Tejido Adiposo Blanco , Proteínas de Unión al ARN , Animales , Masculino , Ratones , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético , Obesidad/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
5.
Cancer Res ; 83(6): 845-860, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36634204

RESUMEN

N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML. SIGNIFICANCE: The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.


Asunto(s)
Leucemia Mieloide Aguda , ARN , Humanos , Animales , Ratones , ARN Mensajero/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Adenosina , Ciclinas , Proteínas de Unión al ARN/genética
6.
Int J Cancer ; 153(1): 20-32, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-36408913

RESUMEN

Most proteins are derived from the translation of coding sequence (CDS) in messenger RNAs (mRNAs). However, accumulating evidence has revealed an unexpected abundance of translation in putative non-coding genomes, especially 5' untranslated region (5' UTR) of mRNAs or non-coding RNA species (ncRNA) such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Notably, many of these UTR- or ncRNA-encoded micropeptides/proteins play important roles in human malignancies. In this review, we describe recent advances in our understanding of the mechanisms underlying the translation of non-coding regions or ncRNAs and the methods to discover the hidden coding information. Furthermore, we summarize the biological functions of UTR- or ncRNA-encoded micropeptides/proteins in cancers and discuss their potential as clinical biomarkers for cancer diagnosis and as therapeutic targets for cancer treatment.


Asunto(s)
Neoplasias , ARN Largo no Codificante , Humanos , ARN no Traducido/genética , ARN Largo no Codificante/genética , Neoplasias/genética , Neoplasias/metabolismo , ARN Mensajero/genética , Proteínas , Micropéptidos
7.
Biochem Biophys Res Commun ; 606: 75-79, 2022 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-35339755

RESUMEN

Hydroxyacyl-CoA dehydrogenase (HADH) catalyzes the third reaction of mitochondrial ß-oxidation cascade, while the regulation of its expression and function remains to be elucidated. Using the quantitative translation initiation sequencing (QTI-seq), we have identified that murine Hadh mRNA has two alternative translation start codons. We demonstrated that translation from upstream start codon encodes the mitochondrial isoform of HADH, while translation from downstream start codon produces a short isoform (HADH-S) with predominant nuclear localization. Moreover, overexpression of HADH-S inhibits the proliferation of mouse embryonic fibroblasts. Overall, our results identify a novel isoform of HADH participating in cell proliferation.


Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas , Fibroblastos , 3-Hidroxiacil-CoA Deshidrogenasas/genética , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Animales , Proliferación Celular , Codón Iniciador , Fibroblastos/metabolismo , Ratones , Isoformas de Proteínas/genética
8.
Genomics ; 114(1): 31-37, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34843904

RESUMEN

Evidence has suggested the potential of tumor-educated platelets as a biomarker trove for cancer diagnostics, but the difficulty in isolation limits its application. Since most of the circulating RNAs are derived from platelets, the change of RNA profile in platelets may lead to altered RNA expression in serum. Here, we identified a panel of platelet-associated long non-coding RNAs (lncRNAs) and evaluated its diagnostic capacity in serum of colorectal cancer (CRC) patients. Four lncRNAs, LNCAROD, SNHG20, LINC00534, and TSPOAP-AS1, were upregulated in both platelets and serum of CRC patients. A binary logistic model derived from them has validated area under roc curve of 0.78 indicating great performance. Furthermore, the expression levels of LNCAROD and TSPOAP-AS1 were correlated with cancer staging and tumor location. Together, our results add novel lncRNA biomarkers to the list of blood tests for CRC diagnostics and provide molecular evidence for the cross-talk between CRC platelets and serum.


Asunto(s)
Ácidos Nucleicos Libres de Células , Neoplasias Colorrectales , ARN Largo no Codificante , Biomarcadores , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , ARN Largo no Codificante/genética , Curva ROC
9.
Aging (Albany NY) ; 13(19): 23119-23132, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34620733

RESUMEN

The anticancer effect of zinc oxide nanoparticles (ZnO NPs) largely relies on cellular responses such as alteration of gene expression. Although ZnO NPs have been reported to induce transcriptional changes, the potential of ZnO NPs to affect cellular translatome remains largely unknown. Using ribosome profiling, we demonstrated that the transcription of 78 genes and the translation of 1,448 genes are affected during one hour of ZnO NPs exposure in A549 human lung cancer cells. The mitogen-activated protein kinase (MAPK) pathway is up-regulated upon ZnO NP treatment. The upstream open reading frame (uORF) plays a pervasive role in the induction of up-regulated genes, including TLNRD1 and CCNB1IP1. Knockdown of TLNRD1 or CCNB1IP1 reduces ZnO NP-induced cytotoxicity. Together, our study characterizes the landscape of translational alteration under ZnO NPs treatment and provides potential targets to augment the anticancer effect of ZnO NPs.


Asunto(s)
Nanopartículas del Metal/química , Ribosomas/efectos de los fármacos , Análisis de Secuencia de ARN/métodos , Óxido de Zinc/farmacología , Células A549 , Estructuras Genéticas , Humanos , Biosíntesis de Proteínas , ARN Mensajero/genética , Ribosomas/genética , Óxido de Zinc/química
10.
Cancer Lett ; 518: 256-265, 2021 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-34339799

RESUMEN

N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNAs, regulates gene expression at the post-transcriptional level. The reader proteins of m6A, mainly YTH domain-containing proteins, specifically recognize m6A-modified mRNAs and regulate their metabolism. Recent studies have highlighted essential roles of m6A readers in the initiation and development of human cancers. In this review, we summarize recent findings about the biological functions of YTH domain proteins in cancers, the underlying mechanisms, and clinical implications. Gene expression reprogramming by dysregulated m6A reader proteins offers potential targets for cancer treatment, while targeted m6A editors and readers provide tools to manipulate m6A metabolism in cancers.


Asunto(s)
Adenosina/análogos & derivados , Neoplasias/genética , Dominios Proteicos/genética , ARN Mensajero/genética , Adenosina/genética , Animales , Expresión Génica/genética , Humanos , Metilación , Procesamiento Postranscripcional del ARN/genética
11.
Life Sci ; 278: 119565, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33965380

RESUMEN

More than one hundred RNA modifications decorate the chemical and topological properties of these ribose nucleotides, thereby executing their biological functions through post-transcriptional regulation. In cardiovascular diseases, a wide range of RNA modifications including m6A (N6-adenosine methylation), m5C (5-methylcytidin), Nm (2'-O-ribose-methylation), Ψ (pseudouridine), m7G (N7-methylguanosine), and m1A (N1-adenosine methylation) have been found in tRNA, rRNA, mRNA and other noncoding RNA, which can function as a novel mechanism in metabolic syndrome, heart failure, coronary heart disease, and hypertension. In this review, we will summarize the current understanding of the regulatory roles and significance of several types of RNA modifications in CVDs (cardiovascular diseases) and the interplay between RNA modifications and noncoding RNA, epigenetics. Finally, we will focus on the potential therapeutic strategies by using RNA modifications.


Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Regulación de la Expresión Génica , ARN/metabolismo , Adenosina/metabolismo , Animales , Aterosclerosis/metabolismo , Enfermedad Coronaria/metabolismo , Epigénesis Genética , Fibrosis/metabolismo , Perfilación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Humanos , Hipertensión Pulmonar/metabolismo , Hipertrofia , Síndrome Metabólico/metabolismo , Metilación , Ratones , Microcirculación , Miocardio/metabolismo , Procesamiento Postranscripcional del ARN , ARN no Traducido/metabolismo , Regeneración , Daño por Reperfusión , Transcriptoma
12.
Biochem Biophys Res Commun ; 557: 85-89, 2021 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-33862464

RESUMEN

N6-methyladenosine (m6A) mRNA modification has been defined as a crucial regulator in various biological processes. Recent studies indicated an essential role of YTHDF1, an m6A reader, in the maintenance of intestinal stem cells (ISCs), while the detailed mechanism remains to be explored. By searching our m6A sequencing, RNA sequencing, and ribosome profiling data, we identified the transcriptional enhanced associate domain 1 (TEAD1) as a direct target of YTHDF1. We confirmed the presence of m6A modifications in TEAD1 mRNA and its binding with YTHDF1. Knockdown of either m6A methyltransferase METTL3 or YTHDF1 reduced the translation of TEAD1. TEAD1 was highly expressed in ISCs, while depletion of TEAD1 inhibited proliferation and induced differentiation of organoids. Overexpression of TEAD1 reversed the impaired stemness elicited by YTHDF1 depletion. These findings identify TEAD1 as a functional target of m6A-YTHDF1 in sustaining intestinal stemness.


Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Intestinos/citología , Proteínas Nucleares/biosíntesis , Proteínas de Unión al ARN/metabolismo , Células Madre/citología , Células Madre/metabolismo , Factores de Transcripción/biosíntesis , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Animales , Línea Celular , Proliferación Celular/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HCT116 , Humanos , Intestinos/fisiología , Metilación , Ratones , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Organoides , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
13.
EMBO J ; 39(13): e103325, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32510170

RESUMEN

Communication between myeloid cells and epithelium plays critical role in maintaining intestinal epithelial barrier integrity. Myeloid cells interact with intestinal epithelial cells (IECs) by producing various mediators; however, the molecules mediating their crosstalk remain incompletely understood. Here, we report that deficiency of angiogenin (Ang) in mouse myeloid cells caused impairment of epithelial barrier integrity, leading to high susceptibility to DSS-induced colitis. Mechanistically, myeloid cell-derived angiogenin promoted IEC survival and proliferation through plexin-B2-mediated production of tRNA-derived stress-induced small RNA (tiRNA) and transcription of ribosomal RNA (rRNA), respectively. Moreover, treatment with recombinant angiogenin significantly attenuated the severity of experimental colitis. In human samples, the expression of angiogenin was significantly down-regulated in patients with inflammatory bowel disease (IBD). Collectively, we identified, for the first time to our knowledge, a novel mediator of myeloid cell-IEC crosstalk in maintaining epithelial barrier integrity, suggesting that angiogenin may serve as a new preventive agent and therapeutic target for IBD.


Asunto(s)
Mucosa Intestinal/metabolismo , Células Mieloides/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Ribonucleasa Pancreática/metabolismo , Transducción de Señal , Animales , Comunicación Celular/genética , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Sulfato de Dextran/toxicidad , Humanos , Mucosa Intestinal/patología , Ratones , Ratones Noqueados , Células Mieloides/patología , Proteínas del Tejido Nervioso/genética , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Ribonucleasa Pancreática/genética
14.
EMBO Rep ; 21(4): e49229, 2020 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-32064749

RESUMEN

N6-methyladenosine (m6 A) mRNA methylation has emerged as an important player in many biological processes by regulating gene expression. However, its roles in intestinal stem cell (ISC) homeostasis remain largely unknown. Here, we report that YTHDF1, an m6 A reader, is highly expressed in ISCs and its expression is upregulated by Wnt signaling at the translational level. Whereas YTHDF1 is dispensable for normal intestinal development in mice, genetic ablation of Ythdf1 dramatically blocks Wnt-driven regeneration and tumorigenesis with reduced ISC stemness. Mechanistically, YTHDF1 facilitates the translation of Wnt signaling effectors including TCF7L2/TCF4, while this process is enhanced during Wnt activation to augment ß-catenin activity. Targeting YTHDF1 in ISCs of established tumors leads to tumor shrinkage and prolonged survival. Collectively, our studies unveil YTHDF1 as an amplifier of Wnt/ß-catenin signaling at the translational level, which is required for the maintenance of ISCs during regeneration and tumorigenesis.


Asunto(s)
Intestinos , Vía de Señalización Wnt , Animales , Carcinogénesis , Transformación Celular Neoplásica , Metilación , Ratones
15.
Int J Biochem Cell Biol ; 113: 95-102, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31220582

RESUMEN

ZnO nanoparticle (ZnO NP) exposure causes oxidative stress in the respiratory system, leading to pulmonary damage. Activating transcription factor 3 (ATF3) participates in a variety of cellular stress responses. However, the role of ATF3 in ZnO NP genotoxicity and cytotoxicity remains to be explored. Here we reported that ZnO NP treatment dramatically induced the expression of ATF3 in human bronchial epithelial (HBE) cells, which was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2). ATF3 was required for the repair of ZnO NP-induced DNA damage as gamma foci number increased when endogenous ATF3 was silenced. Moreover, ATF3 also contributed to ZnO NP-induced cell apoptosis. Mechanistic study revealed that ATF3 interacted with the p53 protein and upregulated its expression under ZnO NP treatment. Collectively, our findings demonstrated ATF3 as an important regulator of epithelial homeostasis by promoting both DNA repair and the death of damaged cells under ZnO NP-induced genotoxic stress.


Asunto(s)
Factor de Transcripción Activador 3/metabolismo , Bronquios/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Nanopartículas/toxicidad , Óxido de Zinc/toxicidad , Factor de Transcripción Activador 3/genética , Apoptosis/efectos de los fármacos , Bronquios/metabolismo , Bronquios/patología , Células Cultivadas , Daño del ADN , Reparación del ADN , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Mutágenos/química , Mutágenos/toxicidad , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Nanopartículas/química , Transcripción Genética/efectos de los fármacos , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética , Óxido de Zinc/química
16.
J Exp Clin Cancer Res ; 38(1): 217, 2019 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-31122284

RESUMEN

BACKGROUND: Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis. METHODS: The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET). RESULTS: Triptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (ApcMin/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA. CONCLUSIONS: Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Diterpenos/administración & dosificación , Fenantrenos/administración & dosificación , Factor de Transcripción TFIIIB/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Diterpenos/farmacología , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Ratones , Fenantrenos/farmacología , Regiones Promotoras Genéticas , ARN Ribosómico 5S , ARN de Transferencia/genética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Cell Death Dis ; 10(2): 127, 2019 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-30755584

RESUMEN

Silica nanoparticles (SiNPs) have been reported to induce pulmonary fibrosis (PF) with an unknown mechanism. Recently, the activation of autophagy, a lysosome-dependent cell degradation pathway, by SiNPs has been identified in alveolar epithelial cells (AECs). However, the underlying mechanism and the relevance of SiNPs-induced autophagy to the development of PF remain elusive. Here, we report that autophagy dysfunction and subsequent apoptosis in AECs are involved in SiNPs-induced PF. SiNPs engulfed by AECs enhance autophagosome accumulation and apoptosis both in vivo and in vitro. Mechanically, SiNPs block autophagy flux through impairing lysosomal degradation via acidification inhibition. Lysosomal reacidification by cyclic-3',5'-adenosine monophosphate (cAMP) significantly enhances autophagic degradation and attenuate apoptosis. Importantly, enhancement of autophagic degradation by rapamycin protects AECs from apoptosis and attenuates SiNPs-induced PF in the mouse model. Altogether, our data demonstrate a repressive effect of SiNPs on lysosomal acidification, contributing to the decreased autophagic degradation in AECs, thus leading to apoptosis and subsequent PF. These findings may provide an improved understanding of SiNPs-induced PF and molecular targets to antagonize it.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Autofagia/efectos de los fármacos , Nanopartículas/administración & dosificación , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Dióxido de Silicio/farmacología , Células A549 , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular , AMP Cíclico/metabolismo , AMP Cíclico/farmacología , Modelos Animales de Enfermedad , Endosomas/metabolismo , Humanos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Ratones , Nanopartículas/efectos adversos , Nanopartículas/química , Transducción de Señal/efectos de los fármacos , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/efectos adversos , Dióxido de Silicio/química , Transfección
18.
Eur J Med Chem ; 162: 122-131, 2019 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-30445262

RESUMEN

A series of novel fusidic acid (FA) derivatives were synthesized and screened for their in vitro cytotoxicity against the Hela, U87, KBV and MKN45 cancer cell lines. Selected FA derivatives with anti-tumor activity were firstly identified including compound 4, which exhibited good anti-proliferative activity with IC50 values in the range of 1.26-3.57 µM. Further research revealed that compound 4 induced Hela cells to undergo apoptosis by increasing the ratio of the cells in the Sub-G0/G1 phase via decreasing the neo-synthesized proteins in a dose-dependent manner from 1 to 10 µM. Compound 4 also showed good in vivo anti-tumor activity against the xenograft tumor of Hela cells and had no apparent toxicity. This study highlights the advantage of introducing the medium-length amino-terminal groups at the 3-OH position of FA to enhance its anti-tumor activity and suggests that compound 4 provides a starting point for designing more potent derivatives in the future.


Asunto(s)
Antineoplásicos/síntesis química , Ácido Fusídico/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ácido Fusídico/síntesis química , Ácido Fusídico/uso terapéutico , Xenoinjertos , Humanos , Ratones , Estructura Molecular , Relación Estructura-Actividad
19.
Angiogenesis ; 22(2): 251-262, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30465119

RESUMEN

The miR-200 family, consisting of miR-200a/b/c, miR-141, and miR-429, is well known to inhibit epithelial-to-mesenchymal transition (EMT) in cancer invasion and metastasis. Among the miR-200 family members, miR-200a/b/c and miR-429 have been reported to inhibit angiogenesis. However, the role of miR-141 in angiogenesis remains elusive, as contradicting results have been found in different cancer types and tumor models. Particularly, the effect of miR-141 in vascular endothelial cells has not been defined. In this study, we used several in vitro and in vivo models to demonstrate that miR-141 in endothelial cells inhibits angiogenesis. Additional mechanistic studies showed that miR-141 suppresses angiogenesis through multiple targets, including NRP1, GAB1, CXCL12ß, TGFß2, and GATA6, and bioinformatics analysis indicated that miR-141 and its targets comprise a powerful and precise regulatory network to modulate angiogenesis. Taken together, these data not only demonstrate an anti-angiogenic effect of miR-141, further strengthening the critical role of miR-200 family in the process of angiogenesis, but also provides a valuable cancer therapeutic target to control both angiogenesis and EMT, two essential steps in tumor growth and metastasis.


Asunto(s)
Redes Reguladoras de Genes/fisiología , MicroARNs/fisiología , Neovascularización Fisiológica/genética , Animales , Células Cultivadas , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/genética , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes/genética , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética
20.
Mol Neurobiol ; 55(2): 1338-1351, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28127696

RESUMEN

Gene defects have been recognized as prominent factors in the etiology and pathogenesis of neurodegeneration. Among 60 neurodegeneration-related mutations in progranulin (PGRN), a mutation in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of its signal peptide at residue 9 (named PGRN A9D) and results in incorrect cytoplasmic sorting. However, the pathogenesis of this mutation remains elusive. To address this issue, we first examined the subcellular distribution of PGRN A9D in human neuronal-like cells (SH-SY5Y). The results showed that PGRN A9D accumulated in cytosolic stress granules. Interestingly, this mis-sorting associated with a cellular redistribution of angiogenin (ANG), a stress-response factor and neurodegenerative disease-related protein, from nucleus to cytoplasmic stress granules, and there existed protein interaction between PGRN A9D and ANG. Further study revealed that the stress granule localization of PGRN A9D was dependent on ANG. Functionally, PGRN A9D abolished the nuclear ANG-mediated biological roles; on the other hand, the relocation of ANG to stress granules activated its cytoprotective stress-response program by cleaving transfer RNAs (tRNAs) to tiRNAs (tRNA-derived, stress-induced small RNAs), thus promoting PGRN A9D cell survival. Taken together, we hypothesize that PGRN A9D leads to the retention of ANG in the cytoplasm to protect cells from PGRN A9D-induced apoptosis, implying that PGRN and ANG act in concert to regulate the progress of neurodegenerative disease.


Asunto(s)
Apoptosis/fisiología , Neuronas/metabolismo , Progranulinas/metabolismo , Ribonucleasa Pancreática/metabolismo , Línea Celular Tumoral , Citosol/metabolismo , Humanos , Mutación , Enfermedades Neurodegenerativas/metabolismo , Progranulinas/genética , ARN de Transferencia
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