ΔNp63α suppresses cell invasion through downregulating Rac1 activity

Abstract

ΔNp63α, a member of the p53 family of transcription factors, is overexpressed in a number of cancers and plays a role in proliferation, differentiation, migration and invasion. We showed previously that ΔNp63α suppresses cell invasion by positively regulating miR‐320a, resulting in the downregulation of its direct target protein kinase C gamma (PKCg) and a corresponding reduction in phosphorylated Ras‐related C3 botulinum toxin substrate 1 (Rac1). Here, we further show that ΔNp63α inhibits Rac1 GTP activity. Using a Rac1 pulldown assay to measure Rac1‐GTP levels, we showed that silencing ΔNp63α in A431 cells led to a significant upregulation of Rac1‐GTP. Silencing ΔNp63α in A431 cells also led to an increase in p21‐activated kinase (PAK1) phosphorylation, confirming the negative regulation of ΔNp63α on Rac1. Inhibiting Rac1 GTP activity using Ehop‐016 led to a significant reduction in both pRac1 and pPAK1 levels. Treatment with Ehop‐016 reversed the increase in cell invasion observed upon silencing ΔNp63α. RT‐PCR analysis performed on an array of 43 Rac guanine exchange factors (Rac‐GEFs) showed that 6 GEFs are significantly upregulated by silencing ΔNp63α in A431 cells. Taken together, our data suggest that ΔNp63α negatively regulates Rac1 GTP activity via downregulation of a Rac‐GEF, thereby reducing Rac1‐GTP levels and inhibiting cancer cell invasion.Support or Funding InformationThis work was supported by a grant from the National Cancer Institute [1R01CA154715] to M.P.K.