ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation

Nat Commun. 2022 Feb 4;13(1):703. doi: 10.1038/s41467-022-28319-3.

Abstract

Rho family mechano-signaling through the actin cytoskeleton positively regulates physiological TEAD/YAP transcription, while the evolutionarily conserved Hippo tumor suppressor pathway antagonizes this transcription through YAP cytoplasmic localization/degradation. The mechanisms responsible for oncogenic dysregulation of these pathways, their prevalence in tumors, as well as how such dysregulation can be therapeutically targeted are not resolved. We demonstrate that p53 DNA contact mutants in human tumors, indirectly hyperactivate RhoA/ROCK1/actomyosin signaling, which is both necessary and sufficient to drive oncogenic TEAD/YAP transcription. Moreover, we demonstrate that recurrent lesions in the Hippo pathway depend on physiological levels of ROCK1/actomyosin signaling for oncogenic TEAD/YAP transcription. Finally, we show that ROCK inhibitors selectively antagonize proliferation and motility of human tumors with either mechanism. Thus, we identify a cancer driver paradigm and a precision medicine approach for selective targeting of human malignancies driven by TEAD/YAP transcription through mechanisms that either upregulate or depend on homeostatic RhoA mechano-signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hippo Signaling Pathway / drug effects
  • Hippo Signaling Pathway / genetics
  • Humans
  • Mice, SCID
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • TEA Domain Transcription Factors / genetics*
  • TEA Domain Transcription Factors / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays / methods
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / genetics*
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • 2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • TEA Domain Transcription Factors
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • YY1AP1 protein, human
  • RHOA protein, human
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • ROCK1 protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein