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ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.
Qian, Chen; Yang, Qian; Rotinen, Mirja; Huang, Rongrong; Kim, Hyoyoung; Gallent, Brad; Yan, Yiwu; Cadaneanu, Radu M; Zhang, Baohui; Kaochar, Salma; Freedland, Stephen J; Posadas, Edwin M; Ellis, Leigh; Di Vizio, Dolores; Morrissey, Colm; Nelson, Peter S; Brady, Lauren; Murali, Ramachandran; Campbell, Moray J; Yang, Wei; Knudsen, Beatrice S; Mostaghel, Elahe A; Ye, Huihui; Garraway, Isla P; You, Sungyong; Freeman, Michael R.
Afiliação
  • Qian C; Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Yang Q; Departments of Urology and Computational Biomedicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Rotinen M; Department of Health Sciences, Public University of Navarre, Pamplona, Navarra, Spain.
  • Huang R; Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA.
  • Kim H; Departments of Urology and Computational Biomedicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Gallent B; Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Yan Y; Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Cadaneanu RM; Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Zhang B; Department of Surgical and Perioperative Care, VA Greater Los Angeles; Department of Urology and Jonsson Comprehensive Cancer Center, the David Geffen School of Medicine, UCLA, Box 951738, 10833 Le Conte Ave 66-188 CHS UCLA, Los Angeles, CA 90095, USA.
  • Kaochar S; Department of Surgical and Perioperative Care, VA Greater Los Angeles; Department of Urology and Jonsson Comprehensive Cancer Center, the David Geffen School of Medicine, UCLA, Box 951738, 10833 Le Conte Ave 66-188 CHS UCLA, Los Angeles, CA 90095, USA.
  • Freedland SJ; Department of Medicine Section Hematology/Oncology Baylor College of Medicine, Houston, 77030 TX, USA.
  • Posadas EM; Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Ellis L; Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Di Vizio D; Center for Prostate Disease Research, Mutha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 2
  • Morrissey C; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • Nelson PS; Departments of Urology, Pathology and Laboratory Medicine, and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Brady L; Department of Urology, University of Washington, Seattle, WA 98195, USA.
  • Murali R; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Campbell MJ; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Yang W; Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Knudsen BS; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Mostaghel EA; Department of Pathology and Cancer Center, Stony Brook University, NY 11794, USA.
  • Ye H; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84108, USA.
  • Garraway IP; Department of Pathology, University of Utah, Salt Lake City, UT 84108, USA.
  • You S; Geriatric Research, Education and Clinical Center (GRECC), U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA 98133, USA.
  • Freeman MR; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Nucleic Acids Res ; 52(13): 7740-7760, 2024 Jul 22.
Article em En | MEDLINE | ID: mdl-38932701
ABSTRACT
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Benzamidas / Adenocarcinoma / Receptores Androgênicos / Receptores de Glucocorticoides / Regulação Neoplásica da Expressão Gênica / Resistencia a Medicamentos Antineoplásicos / Nitrilas Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Benzamidas / Adenocarcinoma / Receptores Androgênicos / Receptores de Glucocorticoides / Regulação Neoplásica da Expressão Gênica / Resistencia a Medicamentos Antineoplásicos / Nitrilas Idioma: En Ano de publicação: 2024 Tipo de documento: Article