ΔNp63α Suppresses TGFB2 Expression and RHOA Activity to Drive Cell Proliferation in Squamous Cell Carcinomas

Cell Reports
Christopher G AbrahamJoaquín M Espinosa

Abstract

The transcriptional repressor ΔNp63α 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 ΔNp63α-dependent cell proliferation, which revealed that the small GTPase RHOA blocks cell division upon ΔNp63α knockdown. After ΔNp63α depletion, RHOA activity is increased, and cells undergo RHOA-dependent proliferation arrest along with transcriptome changes indicative of increased TGF-β signaling. Mechanistically, ΔNp63α 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 ΔNp63α depletion. Genomic data from tumors demonstrate inactivation of RHOA and the TGFBR2 receptor and ΔNp63α overexpression in more than 80% of lung SCCs. These results reveal a signaling pathway controlling SCC proliferation that is potentially amenable to pharmacological intervention.

Citations

Mar 5, 2020·EMBO Molecular Medicine·Cristian Prieto-GarciaMarkus E Diefenbacher
Feb 28, 2020·Cytoskeleton·Nektarios Barabutis
Dec 31, 2018·Aging·Valentina FrezzaFrancesca Bernassola
Nov 23, 2018·International Journal of Molecular Sciences·Yutaro Tsubakihara, Aristidis Moustakas
Nov 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Mingtao ZhangXiao Zhu
Apr 4, 2020·The Journal of Investigative Dermatology·Shakur MohibiXinbin Chen
Feb 28, 2021·The Journal of Pathology·Zuzana PokornáPhilip J Coates

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