ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer

Chen Qian; Qian Yang; Mirja Rotinen; Rongrong Huang; Hyoyoung Kim; Brad Gallent; Yiwu Yan; Radu M Cadaneanu; Baohui Zhang; Salma Kaochar; Stephen J Freedland; Edwin M Posadas; Leigh Ellis; Dolores Di Vizio; Colm Morrissey; Peter S Nelson; Lauren Brady; Ramachandran Murali; Moray J Campbell; Wei Yang; Beatrice S Knudsen; Elahe A Mostaghel; Huihui Ye; Isla P Garraway; Sungyong You; Michael R Freeman

doi:10.1093/nar/gkae547

ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer

Nucleic Acids Res. 2024 Jul 22;52(13):7740-7760. doi: 10.1093/nar/gkae547.

Authors

Chen Qian¹, Qian Yang², Mirja Rotinen³, Rongrong Huang⁴, Hyoyoung Kim², Brad Gallent^{1

5}, Yiwu Yan¹, Radu M Cadaneanu⁶, Baohui Zhang⁶, Salma Kaochar⁷, Stephen J Freedland¹, Edwin M Posadas⁵, Leigh Ellis^{8

9}, Dolores Di Vizio¹⁰, Colm Morrissey¹¹, Peter S Nelson¹², Lauren Brady¹², Ramachandran Murali¹, Moray J Campbell¹³, Wei Yang¹⁴, Beatrice S Knudsen^{15

16}, Elahe A Mostaghel¹⁷, Huihui Ye¹⁸, Isla P Garraway⁶, Sungyong You², Michael R Freeman¹

Affiliations

¹ Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Departments of Urology and Computational Biomedicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Department of Health Sciences, Public University of Navarre, Pamplona, Navarra, Spain.
⁴ Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA.
⁵ Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ 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.
⁷ Department of Medicine Section Hematology/Oncology Baylor College of Medicine, Houston, 77030 TX, USA.
⁸ 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 20814, USA.
⁹ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁰ Departments of Urology, Pathology and Laboratory Medicine, and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹¹ Department of Urology, University of Washington, Seattle, WA 98195, USA.
¹² Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹³ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁴ Department of Pathology and Cancer Center, Stony Brook University, NY 11794, USA.
¹⁵ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84108, USA.
¹⁶ Department of Pathology, University of Utah, Salt Lake City, UT 84108, USA.
¹⁷ Geriatric Research, Education and Clinical Center (GRECC), U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA 98133, USA.
¹⁸ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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.

MeSH terms

Adenocarcinoma* / drug therapy
Adenocarcinoma* / genetics
Adenocarcinoma* / metabolism
Adenocarcinoma* / pathology
Animals
Benzamides* / pharmacology
Cell Line, Tumor
Cell Lineage / genetics
Drug Resistance, Neoplasm* / genetics
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic*
Humans
Male
Mice
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neuroendocrine Tumors / drug therapy
Neuroendocrine Tumors / genetics
Neuroendocrine Tumors / metabolism
Neuroendocrine Tumors / pathology
Nitriles* / pharmacology
Phenylthiohydantoin / analogs & derivatives
Phenylthiohydantoin / pharmacology
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Receptors, Androgen* / genetics
Receptors, Androgen* / metabolism
Receptors, Glucocorticoid* / genetics
Receptors, Glucocorticoid* / metabolism

Substances

Receptors, Androgen
Receptors, Glucocorticoid
enzalutamide
Benzamides
NR3C1 protein, human
Nitriles
SRRM4 protein, human
Phenylthiohydantoin
AR protein, human
Nerve Tissue Proteins
RNA-Binding Proteins

Abstract

MeSH terms

Substances

Grants and funding