Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer

Mark D. Long, Justine J. Jacobi, Prashant K. Singh, Gerard Llimos, Sajad A. Wani, Aryn M. Rowsam, Spencer R. Rosario, Marlous Hoogstraat, Simon Linder, Jason Kirk, Hayley C. Affronti, Andries Bergman, Wilbert Zwart, Moray J. Campbell (Corresponding author), Dominic J. Smiraglia

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Abstract

This study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression in response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival in patients with PC receiving adjuvant ADT. Utilizing the CWR22 xenograft model, we demonstrate that stably reduced NCOR2 expression accelerates disease recurrence following ADT, associates with gene expression patterns that include neuroendocrine features, and induces DNA hypermethylation. Stably reduced NCOR2 expression in isogenic LNCaP (androgen-sensitive) and LNCaP-C4-2 (androgen-independent) cells revealed that NCOR2 reduction phenocopies the impact of androgen treatment and induces global DNA hypermethylation patterns. NCOR2 genomic binding is greatest in LNCaP-C4-2 cells and most clearly associates with forkhead box (FOX) transcription factor FOXA1 binding. NCOR2 binding significantly associates with transcriptional regulation most when in active enhancer regions. These studies reveal robust roles for NCOR2 in regulating the PC transcriptome and epigenome and underscore recent mutational studies linking NCOR2 loss of function to PC disease progression.

Original languageEnglish
Article number110109
Number of pages25
JournalCell Reports
Volume37
Issue number11
DOIs
Publication statusPublished - 14 Dec 2021

Bibliographical note

Funding Information:
M.J.C., D.J.S., and M.D.L. acknowledge support, in part, from the Prostate program of the Department of Defense Congressionally Directed Medical Research Programs ( W81XWH-14-1-0608 ) and the National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Shared Resources, and NCI Cancer Center Support Grant ( P30CA016058 ) to the OSUCCC The James. M.J.C. and G.L. acknowledge support from the European Union-United States Atlantis Program ( P116J090011 ). M.J.C. acknowledges support from the NCI grant awarded to the OSUCCC The James, CCSG, P30CA016058 . M.D.L. acknowledges support from the National Institutes of Health ( U24CA232979 ).

Funding

M.J.C., D.J.S., and M.D.L. acknowledge support, in part, from the Prostate program of the Department of Defense Congressionally Directed Medical Research Programs ( W81XWH-14-1-0608 ) and the National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Shared Resources, and NCI Cancer Center Support Grant ( P30CA016058 ) to the OSUCCC The James. M.J.C. and G.L. acknowledge support from the European Union-United States Atlantis Program ( P116J090011 ). M.J.C. acknowledges support from the NCI grant awarded to the OSUCCC The James, CCSG, P30CA016058 . M.D.L. acknowledges support from the National Institutes of Health ( U24CA232979 ).

FundersFunder number
Department of Defense Congressionally Directed Medical Research ProgramsW81XWH-14-1-0608
European Union-United States Atlantis ProgramP116J090011
National Institutes of Health
National Cancer InstituteP30CA016056, U24CA232979, R21CA121216, P30CA016058

    Keywords

    • epigenome
    • NCOR2
    • neuroendocrine prostate cancer
    • patient-derived xenograft
    • recurrent prostate cancer

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