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

Author:

Qian Chen1ORCID,Yang Qian2,Rotinen Mirja3,Huang Rongrong4,Kim Hyoyoung2,Gallent Brad15,Yan Yiwu1,Cadaneanu Radu M6,Zhang Baohui6,Kaochar Salma7,Freedland Stephen J1,Posadas Edwin M5,Ellis Leigh89,Di Vizio Dolores10,Morrissey Colm11,Nelson Peter S12,Brady Lauren12,Murali Ramachandran1,Campbell Moray J13ORCID,Yang Wei14,Knudsen Beatrice S1516,Mostaghel Elahe A17,Ye Huihui18,Garraway Isla P6,You Sungyong2,Freeman Michael R1

Affiliation:

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

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.

Funder

UCLA Prostate Cancer SPORE

Department of Defense

Institute for Prostate Cancer Research

Publisher

Oxford University Press (OUP)

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