Open AccessDLC1 deficiency and YAP signaling drive endothelial cell contact inhibition of growth and tumorigenesis
Author(s) -
Lisa Ritchey,
TaeKyu Ha,
Atsushi Otsuka,
Kenji Kabashima,
Dunrui Wang,
Yuyi Wang,
Douglas R. Lowy,
Giovanna Tosato
Publication year - 2019
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-019-0944-x
Subject(s) - biology , cell growth , contact inhibition , cancer research , carcinogenesis , effector , tumor suppressor gene , microbiology and biotechnology , cancer , genetics
Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene deleted in many cancers, including angiosarcoma, an aggressive malignancy of endothelial cell derivation. DLC1-deficiency in primary endothelial cells causes the loss of cell contact inhibition of growth through incompletely defined mechanisms. We report that DLC1 is a regulator of YAP, a transcriptional coactivator of proliferation-promoting and tumor-promoting genes; when confluent, active/nuclear YAP was significantly more abundant in DLC1-deficient endothelial cells compared with control cells. We also found that YAP is a required effector of the loss of cell contact inhibition of growth manifested by DLC1-deficient endothelial cells, as the silencing of YAP prevents this loss. Consistently, human angiosarcomas specimens contained a significantly greater proportion of DLC1 - tumor cells with nuclear YAP compared with the DLC1 + normal cells in the adjacent tissue. Verteporfin, an inhibitor of YAP, significantly reduced angiosarcoma growth in mice. These results identify YAP as a previously unrecognized effector of DLC1 deficiency-associated loss of cell contact growth inhibition in endothelial cells and a potential therapeutic target in angiosarcoma.