Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer.
Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer.
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DOI：
10.1016/j.celrep.2021.110109
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发表时间：
2021-12-14
期刊：
影响因子：
8.8
通讯作者：
Smiraglia DJ
中科院分区：
文献类型：
--
作者：
Long MD;Jacobi JJ;Singh PK;Llimos G;Wani SA;Rowsam AM;Rosario SR;Hoogstraat M;Linder S;Kirk J;Affronti HC;Bergman A;Zwart W;Campbell MJ;Smiraglia DJ
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. Long et al. show that reduced levels of NCOR2 lead to accelerated prostate cancer recurrence during androgen withdrawal in a patient-derived xenograft model. NCOR2 reduction is characterized by incomplete response to androgen withdrawal, and recurrent tumors show increased neuroendocrine traits. These phenotypic changes are associated with hypermethylated enhancers.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
3.9
作者：
Campbell MJ
通讯作者：
Campbell MJ
影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA