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; Dominic J. Smiraglia

doi:10.1016/j.celrep.2021.110109

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

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	110109
Number of pages	25
Journal	Cell Reports
Volume	37
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2021.110109
Publication status	Published - 14 Dec 2021

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 ).

Funders	Funder number
National Institutes of Health
National Cancer Institute	P30CA016056, U24CA232979, R21CA121216, P30CA016058

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.110109

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Long, M. D., Jacobi, J. J., Singh, P. K., Llimos, G., Wani, S. A., Rowsam, A. M., Rosario, S. R., Hoogstraat, M., Linder, S., Kirk, J., Affronti, H. C., Bergman, A., Zwart, W., Campbell, M. J., & Smiraglia, D. J. (2021). Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer. Cell Reports, 37(11), Article 110109. https://doi.org/10.1016/j.celrep.2021.110109

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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.",

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AU - Kirk, Jason

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AB - 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.

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Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer

Abstract

Funding

Keywords

UN SDGs

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