Details

Autor(en) / Beteiligte

• 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 R
• 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

Titel

Androgen receptor splice variants drive castrationresistant prostate cancer metastasis by activating distinct transcriptional programs

Ist Teil von

• The Journal of clinical investigation, 2024-06, Vol.134 (11), p.1-19

Ort / Verlag

Ann Arbor: American Society for Clinical Investigation

Erscheinungsjahr

2024

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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.