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

• Published in: Nature communications Vol. 13; no. 1; pp. 703 - 14
• Main Authors: Esposito, Davide, Pant, Ila, Shen, Yao, Qiao, Rui F., Yang, Xiaobao, Bai, Yiyang, Jin, Jian, Poulikakos, Poulikos I., Aaronson, Stuart A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 13; 13/106; 13/89; 14; 14/19; 38; 38/70; 631/67/1059/602; 631/67/395; 64/60; 82/1; Actin; Actomyosin; Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Crosstalk; Cytoskeleton; Deoxyribonucleic acid; DNA; Female; Gene Expression Regulation, Neoplastic - drug effects; Hippo Signaling Pathway - drug effects; Hippo Signaling Pathway - genetics; Humanities and Social Sciences; Humans; Localization; Mice; Mice, SCID; multidisciplinary; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Physiology; Precision medicine; Protein Kinase Inhibitors - pharmacology; Rho-associated kinase; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; RhoA protein; Rocks; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; TEA Domain Transcription Factors - genetics; TEA Domain Transcription Factors - metabolism; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Burden - drug effects; Tumor Burden - genetics; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays - methods; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28319-3

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. Crosstalk between the p53 and Hippo pathway has been reported in different physiological contexts. Here, the authors show that p53 DNA contact mutations upregulate TEAD/YAP transcription indirectly and transform cells via hyperactivation of RhoA/ROCK/actomyosin signaling.