Abstract
Induction of NCOA2 by androgen deprivation enhances prostate cancer progression and metastasis.
Major finding: Induction of NCOA2 by androgen deprivation enhances prostate cancer progression and metastasis.
Mechanism: NCOA2-mediated transcriptional regulation activates PI3K and MAPK signaling to promote CRPC.
Impact: Inhibition of NCOA2-driven signaling combined with androgen deprivation therapy may limit CRPC.
Resistance to androgen deprivation therapy (ADT) results in the outgrowth of castration-resistant prostate cancer (CRPC) and increased metastatic spread. Although PI3K–AKT and MAPK signaling has been implicated in CRPC, the mechanisms that mediate activation of these pathways and progression to CRPC are not completely understood. Nuclear receptor coactivator 2 (NCOA2) is commonly amplified or overexpressed in prostate cancer and is associated with tumor relapse following ADT, prompting Qin, Lee, and colleagues to investigate its potential role in CRPC. Prostate-specific overexpression of NCOA2 was sufficient to initiate prostate epithelial hyperplasia and development of low-grade prostatic intraepithelial neoplasia (PIN) in mice, supporting an oncogenic role for NCOA2. Furthermore, NCOA2 overexpression accelerated the progression of Pten-deficient tumors to high-grade PIN and invasive adenocarcinoma and resulted in enhanced metastatic spread. Ncoa2 expression was suppressed by androgen receptor signaling and induced by androgen deprivation; deletion of Ncoa2 in castrated mice inhibited androgen-independent proliferation and prevented development of CRPC and metastatic disease, suggesting that NCOA2 upregulation in response to ADT is required for CRPC. Mechanistically, NCOA2 directly repressed the transcription of genes that negatively regulate PI3K–AKT signaling, including Phlpp1, Fkbp5, and Pten, and induced the transcription of genes that stimulate the MAPK pathway, including Map3k1 and Prex1, resulting in increased activation of these pathways in prostate tumors and progression to CRPC. Consistent with these findings, expression of an NCOA2 gene expression signature was positively correlated with activation of PI3K and MAPK signaling in human prostate cancer samples and was elevated in patients with metastatic prostate cancer. In addition, high expression of NCOA2-regulated genes was correlated with shorter time to tumor recurrence and decreased survival. These findings identify NCOA2 as a driver of CRPC and prostate cancer metastasis and suggest that inhibition of NCOA2-mediated signaling may enhance the efficacy of ADT.
