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

Article (Faculty180)

cited authors

  • Han, Dong; Labaf, Maryam; Zhao, Yawei; Owiredu, Jude; Zhang, Songqi; Patel, Krishna; Venkataramani, Kavita; Steinfeld, Jocelyn S; Han, Wanting; Li, Muqing; Liu, Mingyu; Wang, Zifeng; Besschetnova, Anna; Patalano, Susan; Mulhearn, Michaela J; Macoska, Jill A; Yuan, Xin; Balk, Steven P; Nelson, Peter S; Plymate, Stephen R; Gao, Shuai; Siegfried, Kellee R; Liu, Ruihua; Stangis, Mary M; Foxa, Gabrielle; Czernik, Piotr J; Williams, Bart O; Zarringhalam, Kourosh; Li, Xiaohong; Cai, Changmeng

description

  • <p>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.</p>

authors

publication date

  • 2024

published in

volume

  • 134