Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.

Race and prostate cancer: genomic landscape.

In the past 20 years, new insights into the genomic pathogenesis of prostate cancer have been provided. Large-scale integrative genomics approaches enabled researchers to characterize the genetic and epigenetic landscape of prostate cancer and to define different molecular subclasses based on the combination of genetic alterations, gene expression patterns and methylation profiles. Several molecular drivers of prostate cancer have been identified, some of which are different in men of different races. However, the extent to which genomics can explain racial disparities in prostate cancer outcomes is unclear. Future collaborative genomic studies overcoming the underrepresentation of non-white patients and other minority populations are essential.

Susceptibility-Associated Genetic Variation in NEDD9 Contributes to Prostate Cancer Initiation and Progression.

Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 (NEDD9) gene, which is strongly associated with increased risk of patients with African ancestry. This genetic variation increased expression of NEDD9 by modulating the chromatin binding of certain transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting prostate cancer tumor growth and metastasis in vitro and in vivo. Together, our study provides novel insights into the genetic mechanisms driving prostate cancer racial disparities. SIGNIFICANCE: A prostate cancer susceptibility genetic variation in NEDD9, which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer.See related commentary by Mavura and Huang, p. 3764.

Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer.

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.

ZBTB7A Mediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate Cancer.

Loss of expression of context-specific tumor suppressors is a critical event that facilitates the development of prostate cancer. Zinc finger and BTB domain containing transcriptional repressors, such as ZBTB7A and ZBTB16, have been recently identified as tumor suppressors that play important roles in preventing prostate cancer progression. In this study, we used combined ChIP-seq and RNA-seq analyses of prostate cancer cells to identify direct ZBTB7A-repressed genes, which are enriched for transcriptional targets of E2F, and identified that the androgen receptor (AR) played a critical role in the transcriptional suppression of these E2F targets. AR recruitment of the retinoblastoma protein (Rb) was required to strengthen the E2F-Rb transcriptional repression complex. In addition, ZBTB7A was rapidly recruited to the E2F-Rb binding sites by AR and negatively regulated the transcriptional activity of E2F1 on DNA replication genes. Finally, ZBTB7A suppressed the growth of castration-resistant prostate cancer (CRPC) in vitro and in vivo, and overexpression of ZBTB7A acted in synergy with high-dose testosterone treatment to effectively prevent the recurrence of CRPC. Overall, this study provides novel molecular insights of the role of ZBTB7A in CRPC cells and demonstrates globally its critical role in mediating the transcriptional repression activity of AR. SIGNIFICANCE: ZBTB7A is recruited to the E2F-Rb binding sites by AR and negatively regulates the transcriptional activity of E2F1 on DNA replication genes.

A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer.

The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again. Importantly, AR mutations are more frequently detected in this type of cancer. By analyzing tumor biopsy mRNA from CRPC patients who had developed resistance to CYP17 inhibitor treatment, we have identified a novel nonsense mutation (Q784*) at the ligand binding domain (LBD) of AR, which produces a C-terminal truncated AR protein that lacks intact LBD. This AR-Q784* mutant is transcriptionally inactive, but it is constitutively expressed in the nucleus and can bind to DNA in the absence of androgen. Significantly, our results show that AR-Q784* can heterodimerize with, and enhance the transcriptional activity of, full-length AR. Moreover, expressing AR-Q784* in an AR positive PCa cell line enhances the chromatin binding of endogenous AR and the recruitment of p300 coactivator under the low androgen condition, leading to increased cell growth. This activity of AR-Q784* mimics the function of some AR splice variants, indicating that CYP17 inhibitor treatment in CRPC may select for LBD-truncated forms of AR to restore AR signaling.