Abstract
The AR splice variant ARv7 binds to full-length AR and represses transcription of CRPC-suppressive genes.
Major finding: The AR splice variant ARv7 binds to full-length AR and represses transcription of CRPC-suppressive genes.
Concept: ARv7 preferentially binds corepressors, suggesting ARv7 and full-length AR have distinct roles in CRPC.
Impact: Understanding the role of ARv7 in CRPC may guide identification of biomarkers of ARv7-dependent tumors.
Expression of androgen receptor (AR) variant 7 (ARv7), a truncated, ligand-independent AR isoform, is associated with androgen-independent cell proliferation and is observed in the majority of patients with castration-resistant prostate cancer (CRPC), but the role of ARv7 in CRPC development is not entirely understood. Cato and colleagues observed that both ARv7 and full-length AR (ARfl) are necessary for CRPC cell proliferation under castration conditions, and the ARv7- and ARfl-dependent transcriptomes are significantly different, suggesting that ARv7 has a distinct role in CRPC and is not simply a constitutively active form of ARfl. Chromatin immunoprecipitation (ChIP) sequencing revealed that ARv7 and ARfl had largely overlapping cistromes, and sequential ARv7/ARfl ChIP–re-ChIP and fluorescence resonance energy transfer suggested that ARv7 and ARfl heterodimerize and co-occupy the same genomic loci. Furthermore, knockdown of one AR isoform reduced chromatin occupancy of the other, suggesting that binding of ARv7 and ARfl to chromatin is codependent. The divergent transcriptomes of ARv7 and ARfl were likely attributable to the observed preferential binding of ARv7 to transcriptional corepressors such as NCOR1 and NCOR2 compared with ARfl and negative regulation of H3K27 acetylation by ARv7 but not ARfl at a subset of shared ARv7/ARfl target genes. Among the genes most specifically repressed by ARv7 were four genes (SLC30A7, B4GALT1, HIF1A, SNX14) shown by CRISPR screen to have a negative effect on CRPC cell proliferation, and low expression of these genes was also associated with shorter recurrence-free survival, metastasis, and prostate cancer–specific mortality. These results are consistent with a model where ARv7 promotes prostate cancer progression through ectopic repression of a subset of AR targets, some with tumor suppressor activity. The expression levels of these genes may serve as biomarkers to determine ARv7 dependence and assess the efficacy of strategies to specifically inhibit ARv7.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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