?Np63? Suppresses TGFB2 Expression and RHOA Activity to Drive Cell Proliferation in Squamous Cell Carcinomas.

ABSTRACT: The transcriptional repressor ?Np63? is a potent oncogene widely overexpressed in squamous cell carcinomas (SCCs) of diverse tissue origins, where it promotes malignant cell proliferation and survival. We report here the results of a genome-wide CRISPR screen to identify pathways controlling ?Np63?-dependent cell proliferation, which revealed that the small GTPase RHOA blocks cell division upon ?Np63? knockdown. After ?Np63? depletion, RHOA activity is increased, and cells undergo RHOA-dependent proliferation arrest along with transcriptome changes indicative of increased TGF-? signaling. Mechanistically, ?Np63? represses transcription of TGFB2, which induces a cell cycle arrest that is partially dependent on RHOA. Ectopic TGFB2 activates RHOA and impairs SCC proliferation, and TGFB2 neutralization restores cell proliferation during ?Np63? depletion. Genomic data from tumors demonstrate inactivation of RHOA and the TGFBR2 receptor and ?Np63? overexpression in more than 80% of lung SCCs. These results reveal a signaling pathway controlling SCC proliferation that is potentially amenable to pharmacological intervention.

SUBMITTER: Abraham CG 

PROVIDER: S-EPMC6219633 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature