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 to the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remains 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.
The Journal of clinical investigation. 2024 Apr 30 [Epub ahead of print]
Dong Han, Maryam Labaf, Yawei Zhao, Jude Owiredu, Songqi Zhang, Krishna Patel, Kavita Venkataramani, Jocelyn S Steinfeld, Wanting Han, Muqing Li, Mingyu Liu, Zifeng Wang, Anna Besschetnova, Susan Patalano, Michaela J Mulhearn, Jill A Macoska, Xin Yuan, Steven P Balk, Peter S Nelson, Stephen R Plymate, Shuai Gao, Kellee R Siegfried, Ruihua Liu, Mary M Stangis, Gabrielle Foxa, Piotr J Czernik, Bart O Williams, Kourosh Zarringhalam, Xiaohong Li, Changmeng Cai
Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, United States of America., Cell and Cancer Biology, The University of Toledo, Toledo, United States of America., Cell and Developmental Biology, Weill Cornell Medical College, New York, United States of America., Biology, University of Massachusetts Boston, Boston, United States of America., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America., Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America., Medicine, University of Washington, Seattle, United States of America., Cell Biology and Anatomy, New York Medical College, Valhalla, United States of America., Cell Biology, Van Andel Institute Core Technologies and Services, Grand Rapids, United States of America., Orthopaedic Surgery, University of Toledo, Toledo, United States of America., Cell and Cancer Biology, University of Toledo, Toledo, United States of America., Center of Personalized Cancer Therapy, University of Massachusetts Boston, Boston, United States of America.