Abstract
YAP is a WW domain‐containing protein that acts as a potent oncogene and stemness factor. It is one of the two main effectors of the Hippo tumor suppressor pathway. YAP is a transforming gene of the chromosome 11q22 amplicon, and its expression is elevated at high frequency in human cancers, including liver, breast, ovarian and stomach cancer. Our recent work showed that YAP regulates the acto‐myosin network by suppressing Rho‐GTPase via Rho‐GTPase activating protein 29 (ARHGAP29) being a direct transcriptional target of YAP in human gastric cancer. We showed that YAP promoted the expression of ARHGAP29 to suppress the RhoA‐LIMK‐cofilin pathway, thereby destabilizing F‐actin. The overexpression of YAP caused cytoskeletal rearrangement by altering the dynamics of F‐actin/G‐actin turnover, thus promoting migration. In a mouse model, circulating tumor cells (CTCs) exhibited an increase in ARHGAP29 RNA level compared with cells at primary tumor sites. Moreover, increased ARHGAP29 expression correlated with shortened survival of human gastric cancer patients. Importantly, we showed that ARHGAP29 is critical in regulating cancer metastasis in a mouse model of liver cancer metastasizing to lungs.We have also identified YAP and TAZ specific transcripts and we are characterizing them now as mechano‐responsive transcripts that regulate cell metastasis and mechano‐sensing.Cancer cells are generally softer than normal cells. By increasing the rigidity of cancer cells to the level of normal cells via novel therapeutic interventions, and by reducing rigidity of extracellular matrix of tumors we could provide a new modality to treat cancer in unison with other standard therapies.Support or Funding InformationStart‐Up Funds from National University of Singapore (R‐185‐000‐2710‐733) and Mechanobiology Institute (R‐714‐018‐006‐271)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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