YAP antagonizes TEAD‐mediated AR signaling and prostate cancer growth. (2nd January 2023)

• Record Type: Journal Article
• Authors: Li, Xu; Zhuo, Shu; Cho, Yong Suk; Liu, Yuchen; Yang, Yingzi; Zhu, Jian; Jiang, Jin
• Is Part Of: EMBO journal. Volume 42:Number 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-02
• Subjects: androgen receptor -- Hippo -- prostate cancer -- TEAD -- YAP; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2022112184
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ‐TEAD transcriptional complex. Here, we uncover a context‐dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR + PCa growth by antagonizing TEAD‐mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR‐TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of MST1/2 or LATS1/2, or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR + PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants. Synopsis: Deviating from its established oncogenic function, this study uncovers a context‐dependent tumor suppressor role of Hippo signalling pathway effector YAP in androgen receptor (AR)‐positive prostate cancer (PCa), and unexpected crosstalk between Hippo and AR signalling. TEAD forms a transcriptional complex with AR in PCa increasing its promoter and enhancer occupancy. Elevated nuclear YAP inhibits AR activity by competing for TEAD binding. Small molecule Hippo pathway inhibition or transgenic YAP activation decrease AR + PCa growth. Abstract : Hippo pathway effector YAP acts as a tumor suppressor in prostate cancer, competing with androgen receptor for TEAD binding.