Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs
Dong Han, … , Xiaohong Li, Changmeng Cai
Dong Han, … , Xiaohong Li, Changmeng Cai
Published April 30, 2024
Citation Information: J Clin Invest. 2024;134(11):e168649. https://doi.org/10.1172/JCI168649.
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Research Article Oncology

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

Abstract

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.

Authors

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

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Figure 4

AR-V7 can bind to a subset of chromatin sites distinct from AR-FL binding.

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AR-V7 can bind to a subset of chromatin sites distinct from AR-FL bindin...
(A and B) ChIP-seq analysis of V5 was conducted in LN-tet-ARV7 cells (hormone depleted) stimulated with or without 0.25 μg/mL doxycycline for 48 hours. Similarly, ChIP-seq analysis of AR (antibody against N-terminus) was performed in LN-tet-ARFL cells stimulated with 0.25 μg/mL doxycycline and then treated with 0.1 nM DHT for 4 hours. The Venn diagram (A) and heatmap view (B) demonstrate the unique or overlapping sites of AR-V7 versus AR-FL. (C–E) Binding and expression target analysis (BETA) was used to assess the association of total AR-V7 sites with AR-V7–regulated genes (C), total AR-FL sites with androgen-upregulated genes (D), and the unique or common sites of AR-FL/AR-V7 with androgen-upregulated genes or AR-V7–regulated genes (E). P values were calculated by BETA as a measure of the significance of the association between transcription factor binding and gene expression changes. (F) Motif enrichment analyses were conducted for the AR-FL/AR-V7 unique or common sites and ranked by z score (black, common enriched motifs; purple, uniquely enriched motifs).