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1.
Sci Immunol ; 7(74): eabj9123, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35930654

RESUMO

Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8+ T cells throughout differentiation. We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential. Terminally exhausted T cells had a substantial fraction of active chromatin, including active enhancers enriched for bZIP/AP-1 transcription factor motifs that lacked correlated gene expression, which was restored by immunotherapeutic costimulatory signaling. Reduced transcriptional potential was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Enforced expression of the hypoxia-insensitive histone demethylase Kdm6b was sufficient to overcome hypoxia, increase function, and promote antitumor immunity. Our study reveals the specific epigenetic changes mediated by histone modifications during T cell differentiation that support exhaustion in cancer, highlighting that their altered function is driven by improper costimulatory signals and environmental factors. These data suggest that even terminally exhausted T cells may remain competent for transcription in settings of increased costimulatory signaling and reduced hypoxia.


Assuntos
Cromatina , Neoplasias , Linfócitos T CD8-Positivos , Cromatina/metabolismo , Histonas/metabolismo , Humanos , Hipóxia/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Microambiente Tumoral
2.
Proc Natl Acad Sci U S A ; 119(32): e2201483119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35930668

RESUMO

The Jumonji domain-containing protein JMJD6 is a 2-oxoglutarate-dependent dioxygenase associated with a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing, and cotranscriptional processing. Although not all studies agree, JMJD6 has been reported to catalyze both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and indirect evidence for JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a reported site of proline hydroxylation within a lysine-rich region of the tandem bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalyzed by JMJD6. This prompted a wider search for JMJD6-catalyzed protein modifications deploying mass spectrometric methods designed to improve the analysis of such lysine-rich regions. Using lysine derivatization with propionic anhydride to improve the analysis of tryptic peptides and nontryptic proteolysis, we report 150 sites of JMJD6-catalyzed lysine hydroxylation on 48 protein substrates, including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some, multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in these studies have been associated with membraneless organelle formation. Given the reported roles of lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia.


Assuntos
Proteínas Intrinsicamente Desordenadas , Lisina , Hidroxilação , Proteínas Intrinsicamente Desordenadas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Domínios Proteicos , Fatores de Transcrição/metabolismo
3.
Clin Epigenetics ; 14(1): 98, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915507

RESUMO

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.


Assuntos
Histonas , Neoplasias , Metilação de DNA , Epigênese Genética , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lisina/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética
4.
Int J Mol Sci ; 23(14)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35887017

RESUMO

The Jumonji-C (JmjC) family of lysine demethylases (KDMs) (JMJC-KDMs) plays an essential role in controlling gene expression and chromatin structure. In most cases, their function has been attributed to the demethylase activity. However, accumulating evidence demonstrates that these proteins play roles distinct from histone demethylation. This raises the possibility that they might share domains that contribute to their functional outcome. Here, we show that the JMJC-KDMs contain low-complexity domains and intrinsically disordered regions (IDR), which in some cases reached 70% of the protein. Our data revealed that plant homeodomain finger protein (PHF2), KDM2A, and KDM4B cluster by phase separation. Moreover, our molecular analysis implies that PHF2 IDR contributes to transcription regulation. These data suggest that clustering via phase separation is a common feature that JMJC-KDMs utilize to facilitate their functional responses. Our study uncovers a novel potential function for the JMJC-KDM family that sheds light on the mechanisms to achieve the competent concentration of molecules in time and space within the cell nucleus.


Assuntos
Histona Desmetilases , Histona Desmetilases com o Domínio Jumonji , Núcleo Celular/metabolismo , Desmetilação , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/metabolismo
5.
Theranostics ; 12(11): 4922-4934, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35836814

RESUMO

Rationale: Traditional treatments for leukemia fail to address stem cell drug resistance characterized by epigenetic mediators such as histone lysine-specific demethylase 4 (KDM4). The KDM4 family, which acts as epigenetic regulators inducing histone demethylation during the development and progression of leukemia, lacks specific molecular inhibitors. Methods: The KDM4 inhibitor, SD49-7, was synthesized and purified based on acyl hydrazone Schiff base. The interaction between SD49-7 and KDM4s was monitored in vitro by surface plasma resonance (SPR). In vitro and in vivo biological function experiments were performed to analyze apoptosis, colony-formation, proliferation, differentiation, and cell cycle in cell sub-lines and mice. Molecular mechanisms were demonstrated by RNA-seq, ChIP-seq, RT-qPCR and Western blotting. Results: We found significantly high KDM4A expression levels in several human leukemia subtypes. The knockdown of KDM4s inhibited leukemogenesis in the MLL-AF9 leukemia mouse model but did not affect the survival of normal human hematopoietic cells. We identified SD49-7 as a selective KDM4 inhibitor that impaired the progression of leukemia stem cells (LSCs) in vitro. SD49-7 suppressed leukemia development in the mouse model and patient-derived xenograft model of leukemia. Depletion of KDM4s activated the apoptosis signaling pathway by suppressing MDM2 expression via modulating H3K9me3 levels on the MDM2 promoter region. Conclusion: Our study demonstrates a unique KDM4 inhibitor for LSCs to overcome the resistance to traditional treatment and offers KDM4 inhibition as a promising strategy for resistant leukemia therapy.


Assuntos
Histonas , Leucemia Mieloide Aguda , Animais , Ciclo Celular , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Leucemia Mieloide Aguda/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Células-Tronco/metabolismo
6.
Int J Biol Sci ; 18(9): 3621-3635, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813477

RESUMO

The poor sensitivity of clear cell renal cell carcinoma (ccRCC) to conventional chemotherapy and radiotherapy makes its treatment challenging. The Ndc80 kinetochore complex component (NUF2) is involved in the development and progression of several cancers. However, its role in ccRCC remains unclear. In this study, we investigated the biological functions and underlying mechanism of NUF2 in ccRCC. We found that NUF2 expression was increased in ccRCC and associated with poor prognosis. Altering NUF2 level affected cell proliferation, migration, and invasion. Moreover, NUF2 acted as a potential oncogene to promote the progression of ccRCC through epigenetic activation of high-mobility group AT-hook 2 (HMGA2) transcription by suppressing lysine demethylase 2A expression and affecting its occupancy on the HMGA2 promoter region to regulate histone H3 lysine 36 di-methylation modification. In addition, Kaplan-Meier and multivariate analysis revealed that patients whose NUF2 and HMGA2 were both elevated showed the shortest survival; and the number of upregulated markers acted as an independent predictor to evaluate survival probability. Thus, our results demonstrate that NUF2 promotes ccRCC progression, at least partly by epigenetically regulating HMGA2 transcription, and that the NUF2-HMGA2 axis could be an ideal therapeutic target and a promising prognostic indicator for ccRCC.


Assuntos
Carcinoma de Células Renais , Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box , Neoplasias Renais , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Desmetilação , Proteínas F-Box/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Renais/metabolismo , Lisina/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-35840288

RESUMO

INTRODUCTION: Alterations in the genes of lysine methylation as Lysine-specific demethylase 6B (KDM6B) have been associated with multiple neurodevelopmental disorders. Until now, there are few cases in the literature attributed to KDM6B mutations. This gap may be due to the fact that the exome sequencing technique is still being implemented in routine clinical practice. MATERIAL AND METHODS: A case is presented with its clinical and phenotypic characteristics. The sequence exome analysis was done with the Nimblegen SeqCap EZ MedExome capture kit+mtDNA 47Mb. The psychopathological approach from mental health was carried out through individual and family interviews, the Conner's questionnaires, ADHD rating scale, as well as the psychometry. RESULTS: A frameshift variant in the KDM6B gene related to neurodevelopmental disorders with facial and body dysmorphia was obtained. The case was oriented as a neurodevelopmental disorder secondary to a genetic alteration and a comorbid Attention Deficit Hyperactivity Disorder (ADHD). CONCLUSIONS: The clinical peculiarities shared by patients identified with the KDM6B mutation, raises the need to recognize it as a particular entity. The possibility of applying the exome sequencing technique to patients with syndromic phenotype and developmental impairment may clarify its etiopathogenesis. It is highly probable that the complexity of these cases requires an approach by a multidisciplinary team that includes genetics, neurology and psychiatry, among other specialties. The coordinated approach is essential to have a comprehensive vision of the case.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtornos do Neurodesenvolvimento , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lisina , Mutação , Fenótipo
8.
Int J Oral Sci ; 14(1): 34, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35831280

RESUMO

Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.


Assuntos
Cartilagem Articular , Histona Desmetilases com o Domínio Jumonji , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Osteoartrite , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Regulação para Baixo , Epigênese Genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacologia
9.
Contrast Media Mol Imaging ; 2022: 4657952, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35833065

RESUMO

This study investigates the mechanism of hsa_circ_0001429 adsorbing miR-205 and regulating the expression of KDM4A to promote breast cancer metastasis and its mechanism. Mammary epithelial cells MCF-10A and human breast cancer cell lines BT474, SKBr-3, ZR-75-30, and MCF7 are cultured, and the mRNA expressions of hsa_circ_000 1429, miR-205, and KDM4A are detected by qRT-PCR; hsa_circ_000 1429 binds to miR-205, and miR-205 targets KDM4A. RIP verifies that hsa_circ_000 1429 binds to AGO2; RNA pull down results prove that hsa_circ_000 1429 binds to miR-205; MTT detects cell proliferation; transwell assay detects cell migration and invasion ability; flow cytometry detects cell apoptosis rate. The expressions of KDM4A, migration, and invasion-related factors, N-cadherin and MMP-9 protein, are detected by blot. hsa_circ_000 1429 may upregulate the KDM4A gene by adsorbing miR-205. Therefore, it will promote the proliferation, migration, and invasion of breast cancer cells and inhibit their apoptosis.


Assuntos
Neoplasias da Mama , Histona Desmetilases com o Domínio Jumonji , MicroRNAs , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
10.
Sci Transl Med ; 14(653): eabq2096, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35857643

RESUMO

Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1+ RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.


Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição Box Pareados/uso terapêutico , Rabdomiossarcoma/genética , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia
11.
J Med Chem ; 65(14): 9564-9579, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35838529

RESUMO

The histone lysine demethylase 4 (KDM4) family plays an important role in regulating gene transcription, DNA repair, and metabolism. The dysregulation of KDM4 functions is associated with many human disorders, including cancer, obesity, and cardiovascular diseases. Selective and potent KDM4 inhibitors may help not only to understand the role of KDM4 in these disorders but also to provide potential therapeutic opportunities. Here, we provide an overview of the field and discuss current status, challenges, and opportunities lying ahead in the development of KDM4-based anticancer therapeutics.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases com o Domínio Jumonji , Neoplasias , Histona Desmetilases/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias/tratamento farmacológico
12.
Int J Mol Sci ; 23(14)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35887001

RESUMO

JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Pontos de Checagem do Ciclo Celular , Histona Desmetilases , Histona Desmetilases com o Domínio Jumonji , Neoplasias Hepáticas , Aminopiridinas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Histona Desmetilases/farmacologia , Histonas/metabolismo , Humanos , Hidrazonas , Histona Desmetilases com o Domínio Jumonji/farmacologia , Histona Desmetilases com o Domínio Jumonji/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Lisina/metabolismo , Recidiva Local de Neoplasia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
13.
Front Immunol ; 13: 875786, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35898493

RESUMO

Background: JMJD8 has recently been identified as a cancer-related gene, but current studies provide limited information. We aimed to clarify its roles and the potential mechanisms in pan-cancer. Methods: Pan-cancer bulk sequencing data and online web tools were applied to analyze JMJD8's correlations with prognosis, genome instability, cancer stemness, DNA repair, and immune infiltration. Moreover, single-cell datasets, SpatialDB database, and multiple fluorescence staining were used to validate the association between JMJD8 expression and M2 macrophages. Further, we utilized ROCplotter and cMap web tool to analyze the therapeutic responses and screened JMJD8-targeted compounds, respectively, and we used AlphaFold2 and Discovery Studio to conduct JMJD8 homology modeling and molecular docking. Results: We first noticed that JMJD8 was an oncogene in many cancer types. High JMJD8 was associated with lower genome stability. We then found that high JMJD8 correlated with high expression of mismatch repair genes, stemness, homologous repair gene signature in more than 9 cancers. ESTIMATE and cytokine analyses results presented JMJD8's association with immunosuppression. Also, immune checkpoint CD276 was positively relevant to JMJD8. Subsequently, we validated JMJD8 as the M2 macrophage marker and showed its connection with other immunosuppressive cells and CD8+ T-cell depression. Finally, potential JMJD8-targeted drugs were screened out and docked to JMJD8 protein. Conclusion: We found that JMJD8 was a novel oncogene, and it correlated with immunosuppression and DNA repair. JMJD8 was highly associated with immune checkpoint CD276 and was an M2 macrophage biomarker in many cancers. This study will reveal JMJD8's roles in pan-cancer and its potential as a novel therapeutic target.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias , Antígenos B7/genética , Biomarcadores , Dano ao DNA , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Terapia de Imunossupressão , Macrófagos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética
14.
Endocrinology ; 163(9)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35881915

RESUMO

OBJECTIVE: Abnormal expression of CUT-like homeobox 2 gene (CUX2) has been highlighted as potential clinical biomarkers in human cancers. Notably, the function of CUX2 has been less elucidated in breast cancer (BC). We focused on the role of the CUX2 in tumorigenesis and progression of BC with the involvement of the lysine demethylase 5B (KDM5B)/sex determining region Y-box 17 (SOX17) axis. METHODS: CUX2, KDM5B, and SOX17 expression levels in BC tissues and cells were tested by reverse transcription quantitative PCR and Western blotting. Later, the effects of CUX2, KDM5B, and SOX17 on the malignant behaviors of MDA-MB-231 and MCF-7 cells were analyzed by CCK-8, colony formation, and Transwell assays in vitro. The interactions of CUX2, KDM5B, and SOX17 were validated by online website prediction, ChIP assay, and dual luciferase reporter gene assay. The subcutaneous tumorigenesis in nude mice was conducted to observe the roles of CUX2, KDM5B, and SOX17 in BC tumor growth in vivo. RESULTS: CUX2 and KDM5B were highly expressed while SOX17 had low expression in BC. Inhibition of CUX2 suppressed BC cell malignant phenotypes. CUX2 promoted KDM5B expression through transcriptional activation, enabling its high expression in BC. KDM5B inhibited SOX17 expression through histone demethylation. Overexpression of KDM5B or downregulation of SOX17 reversed the inhibitory effect of CUX2 downregulation on the malignant behaviors of BC cells. Inhibition of CUX2 impeded BC cell growth in vivo through the KDM5B/SOX17 axis. CONCLUSION: This study highlights that suppression of CUX2 inhibits KDM5B to repress tumorigenesis and progression of BC through overexpressing SOX17.


Assuntos
Neoplasias da Mama , MicroRNAs , Animais , Neoplasias da Mama/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas HMGB , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Nus , MicroRNAs/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo
15.
Mol Biol Rep ; 49(8): 7239-7249, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35788877

RESUMO

BACKGROUND: Studies have shown that histone H3 methylation is involved in regulating the differentiation of Bone Marrow Mesenchymal Stem Cells (BMSCs). KDM5B can specifically reduce the level of histone 3 lysine 4 trimethylation (H3K4me3), thereby activating the expression of related genes and participating in biological processes such as cell differentiation, embryonic development and tumor formation. Whether KDM5B is involved in the regulation of BMSCs differentiation into cardiomyocytes through the above manner has not been reported. OBJECTIVE: To investigate the effect of KDM5B on the induction and differentiation of swine BMSCs into myocardial cells in vitro. METHODS: Swine bone marrow BMSCs were isolated and cultured, and the overexpression, interference expression and blank vector of KMD5B were constructed and transfected by lentivirus. BMSCs was induced to differentiate into cardiomyocytes by 5-azacytidine (5-AZA) in vitro, and the differentiation efficiency was compared by immunofluorescence, RT-PCR, Western Blot and whole-cell patch clamp detection. RESULT: Compared with the control group, the expression levels of histone H3K4me3 and pluripotency gene Nanog in KDM5B overexpression group were significantly decreased, while the expression level of key myocardial gene HCN4 and myocardial marker gene α-Actin and cTNT were significantly increased, and the Na+ current density on the surface of differentiated myocardial cell membrane was significantly increased. Meanwhile, the corresponding results of the KDM5B silent expression group were just opposite. CONCLUSIONS: It indicated that enhanced KDM5B expression could promote the differentiation of BMSCs into cardiomyocytes and improve the differentiation efficiency by controlling H3K4 methylation levels.


Assuntos
Histonas , Células-Tronco Mesenquimais , Animais , Células da Medula Óssea/metabolismo , Catálise , Diferenciação Celular/genética , Células Cultivadas , Desmetilação , Histona Desmetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células-Tronco Mesenquimais/metabolismo , Miócitos Cardíacos/metabolismo , Suínos
16.
Cell Death Dis ; 13(6): 547, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35697678

RESUMO

Epigenetic dysregulation contributes to bladder cancer tumorigenesis. H3K36me2 demethylase KDM2A functions as an important epigenetic regulator of cell fate in many types of tumors. However, its role in bladder cancer remains unknown. Here, we revealed a positive correlation between KDM2A gene copy number gain and upregulation of KDM2A mRNA expression in bladder cancer. Moreover, a super-enhancer (SE) driving KDM2A transcription was found in high-grade bladder cancer, resulting in a significantly higher expression of KDM2A mRNA compared to that in low-grade bladder tumors. KDM2A knockdown (KD) decreased the proliferation, invasion, and spheroid formation of high-grade bladder cancer cells and inhibited tumor growth in mouse xenograft models. Furthermore, we identified RARRES3 as a key KDM2A target gene. KDM2A suppresses RARRES3 expression via demethylation of H3K36me2 in the RARRES3 promoter. Intriguingly, RARRES3 KD attenuated the inhibitory effects of KDM2A depletion on the malignant phenotypes of high-grade bladder cancer cells. The combination of the KDM2A inhibitor IOX1 and the RARRES3 agonist all-trans retinoic acid (ATRA) synergistically inhibited the proliferation of high-grade bladder cancer cells, suggesting that the KDM2A/RARRES3 axis may be a promising therapeutic target for the treatment of high-grade bladder cancer.


Assuntos
Proteínas F-Box , Receptores do Ácido Retinoico/genética , Neoplasias da Bexiga Urinária , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas F-Box/metabolismo , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , RNA Mensageiro/genética , Neoplasias da Bexiga Urinária/genética
17.
Biomed Res Int ; 2022: 3742447, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757472

RESUMO

Glioma is one of the most common intracranial malignancies that plagues people around the world. Despite current improvements in treatment, the prognosis of glioma is often unsatisfactory. Necroptosis is a form of programmed cell death. As research progresses, the role of necroptosis in tumors has gradually attracted the attention of researchers. And lncRNA is regarded as a critical role in the development of cancer. Therefore, this study is aimed at establishing a prognostic model based on necroptosis-associated lncRNAs to accurately assess the prognosis and immune response of patients with glioma. The RNA sequences of glioma patients and normal brain samples were downloaded from The Cancer Genome Atlas (TCGA) and GTEx databases, respectively. The coexpression analysis was performed to identify the necroptosis-related lncRNAs. Then, we utilized LASSO analysis following univariate Cox analysis to construct a prognostic model. Subsequently, we applied the Kaplan-Meier curve, time-dependent receiver operating characteristics (ROC), and univariate and multivariate Cox regression analyses to assess the effectiveness of this model. And the functional enrichment analyses and immune-related analyses were employed to investigate the potential biological functions. A validation set was obtained from the Chinese Glioma Genome Atlas (CGGA) database. And qRT-PCR was employed to further validate the expression levels of selected necroptosis-associated lncRNAs. Seven necroptosis-related lncRNAs (FAM13A-AS1, JMJD1C-AS1, LBX2-AS1, ZBTB20-AS4, HAR1A, SNHG14, and LINC00900) were determined to construct a prognostic model. The area under the ROC curve (AUC) was 0.871, 0.901, and 0.911 at 1, 2, and 3 years, respectively. The risk score was shown to be an important independent predictor in both univariate and multivariate Cox regression analyses. Through functional enrichment analyses, we found that the differentially expressed genes (DEGs) were mainly enriched in protein binding and signaling-related biological functions and immune-associated pathways. In conclusion, we established and validated a novel necroptosis-related lncRNA signature, which could accurately predict the overall survival of glioma patients and serve as potential therapeutic targets.


Assuntos
Glioma , RNA Longo não Codificante , Biomarcadores Tumorais/genética , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Imunidade , Histona Desmetilases com o Domínio Jumonji/genética , Estimativa de Kaplan-Meier , Necroptose/genética , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Prognóstico , RNA Longo não Codificante/metabolismo
18.
Leukemia ; 36(7): 1843-1849, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35654819

RESUMO

Mutations of the JAK2 gene are frequent aberrations in the aging hematopoietic system and in myeloid neoplasms. While JAK-inhibitors efficiently reduce hyperinflammation induced by the constitutively active mutated JAK2 kinase, the malignant clone and abundance of mutated cells remains rather unaffected. Here, we sought to assess for genetic vulnerabilities of JAK2-mutated clones. We identified lysine-specific demethylase KDM4C as a selective genetic dependency that persists upon JAK-inhibitor treatment. Genetic inactivation of KDM4C in human and murine JAK2-mutated cells resulted in loss of cell competition and reduced proliferation. These findings led to reduced disease penetrance and improved survival in xenograft models of human JAK2-mutated cells. KDM4C deleted cells showed alterations in target histone residue methylation and target gene expression, resulting in induction of cellular senescence. In summary, these data establish KDM4C as a specific dependency and therapeutic target in JAK2-mutated cells that is essential for oncogenic signaling and prevents induction of senescence.


Assuntos
Histona Desmetilases , Neoplasias , Animais , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Metilação , Camundongos , Neoplasias/genética , Transdução de Sinais
19.
Leukemia ; 36(8): 2097-2107, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35697791

RESUMO

Loss-of-function TET2 mutations are recurrent somatic lesions in chronic myelomonocytic leukemia (CMML). KDM6B encodes a histone demethylase involved in innate immune regulation that is overexpressed in CMML. We conducted genomic and transcriptomic analyses in treatment naïve CMML patients and observed that the patients carrying both TET2 mutations and KDM6B overexpression constituted 18% of the cohort and 42% of patients with TET2 mutations. We therefore hypothesized that KDM6B overexpression cooperated with TET2 deficiency in CMML pathogenesis. We developed a double-lesion mouse model with both aberrations, and discovered that the mice exhibited a more prominent CMML-like phenotype than mice with either Tet2 deficiency or KDM6B overexpression alone. The phenotype includes monocytosis, anemia, splenomegaly, and increased frequencies and repopulating activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Significant transcriptional alterations were identified in double-lesion mice, which were associated with activation of proinflammatory signals and repression of signals maintaining genome stability. Finally, KDM6B inhibitor reduced BM repopulating activity of double-lesion mice and tumor burden in mice transplanted with BM-HSPCs from CMML patients with TET2 mutations. These data indicate that TET2 deficiency and KDM6B overexpression cooperate in CMML pathogenesis of and that KDM6B could serve as a potential therapeutic target in this disease.


Assuntos
Proteínas de Ligação a DNA , Dioxigenases , Histona Desmetilases com o Domínio Jumonji , Leucemia Mielomonocítica Crônica , Leucemia Mielomonocítica Juvenil , Animais , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/deficiência , Dioxigenases/genética , Dioxigenases/metabolismo , Perfilação da Expressão Gênica , Genoma , Humanos , Histona Desmetilases com o Domínio Jumonji/biossíntese , Histona Desmetilases com o Domínio Jumonji/genética , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Mutação com Perda de Função , Camundongos , Mutação , Proteínas Proto-Oncogênicas/genética
20.
Int J Oral Sci ; 14(1): 24, 2022 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-35525910

RESUMO

Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.


Assuntos
Envelhecimento , Ossos Faciais , Histona Desmetilases com o Domínio Jumonji , Células-Tronco Mesenquimais , Osteogênese , Osteoporose , Diferenciação Celular , Ossos Faciais/citologia , Ossos Faciais/fisiologia , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Células-Tronco Mesenquimais/citologia
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