2. Academic Validation
  3. YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth

YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth

  • EMBO J. 2023 Jan 2;e112184. doi: 10.15252/embj.2022112184.
Xu Li # 1,  Shu Zhuo # 1 2,  Yong Suk Cho # 1,  Yuchen Liu 3 4 5,  Yingzi Yang 3 4 5,  Jian Zhu 1 6,  Jin Jiang 1 7
Affiliations

Affiliations

  • 1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Center for Cancer Targeted Therapies, Signet Therapeutics Inc., Research Institute of Tsinghua University in Shenzhen, Shenzhen, China.
  • 3 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
  • 4 Harvard Stem Cell Institute, Boston, MA, USA.
  • 5 Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
  • 6 Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 7 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • # Contributed equally.
PMID: 36588499 DOI: 10.15252/embj.2022112184
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.

Keywords

Hippo; TEAD; YAP; androgen receptor; prostate cancer.

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