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1.
Cancer Res ; 81(4): 1087-1100, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33822745

RESUMO

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.


Assuntos
Histona Desmetilases com o Domínio Jumonji/fisiologia , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Processamento Alternativo , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Terapia de Alvo Molecular , Oxigenases/genética , Oxigenases/fisiologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Estudos Retrospectivos
2.
Cancer Discov ; 11(5): 1118-1137, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33431496

RESUMO

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Imidazóis/uso terapêutico , Oxazóis/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Oxazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Dis Model Mech ; 9(12): 1483-1495, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27799148

RESUMO

Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eµ). Here, we report that the Eµ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eµ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.


Assuntos
Linfócitos B/enzimologia , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Linfoma de Células B/enzimologia , Linfoma de Células B/genética , Transtornos Linfoproliferativos/enzimologia , Transtornos Linfoproliferativos/genética , Proteínas Repressoras/genética , Acetilação , Animais , Linfócitos B/patologia , Ciclo Celular/genética , Perfilação da Expressão Gênica , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Células HeLa , Histona Desacetilases/metabolismo , Humanos , Linfoma de Células B/patologia , Transtornos Linfoproliferativos/patologia , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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