ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a

• Published in: Cell death & disease 2019-09, Vol.10 (9), p.680-14, Article 680
• Main Authors: Aljagthmi, Amjad A., Hill, Natasha T., Cooke, Mariana, Kazanietz, Marcelo G., Abba, Martín C., Long, Weiwen, Kadakia, Madhavi P.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/95; 38/109; 38/77; 631/67/395; 631/80/86; 82/29; 82/80; Antibodies; Biochemistry; Biomedical and Life Sciences; Blotting, Western; Cancer; Cell Biology; Cell Culture; Cell Line, Tumor; Colorectal cancer; Colorectal carcinoma; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Guanosine triphosphatases; Humans; Immunology; Kinases; Life Sciences; Metastases; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; p53 Protein; Phosphorylation; Phosphorylation - genetics; Phosphorylation - physiology; Protein kinase C; Protein Kinase C-delta - genetics; Protein Kinase C-delta - metabolism; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Real-Time Polymerase Chain Reaction; Signal Transduction - genetics; Signal Transduction - physiology; Transcription factors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Wnt protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1921-6

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. ΔNp63α has been shown to regulate several microRNAs that are involved in development and cancer. We identified miRNA miR-320a as a positively regulated target of ΔNp63α. Previous studies have shown that miR-320a is downregulated in colorectal cancer and targets the small GTPase Rac1, leading to a reduction in noncanonical WNT signaling and EMT, thereby inhibiting tumor metastasis and invasion. We showed that miR-320a is a direct target of ΔNp63α. Knockdown of ΔNp63α in HaCaT and A431 cells downregulates miR-320a levels and leads to a corresponding elevation in PKCγ transcript and protein levels. Rac1 phosphorylation at Ser71 was increased in the absence of ΔNp63α, whereas overexpression of ΔNp63α reversed S71 phosphorylation of Rac1. Moreover, increased PKCγ levels, Rac1 phosphorylation and cell invasion observed upon knockdown of ΔNp63α was reversed by either overexpressing miR-320a mimic or Rac1 silencing. Finally, silencing PKCγ or treatment with the PKC inhibitor Gö6976 reversed increased Rac1 phosphorylation and cell invasion observed upon silencing ΔNp63α. Taken together, our data suggest that ΔNp63α positively regulates miR-320a, thereby inhibiting PKCγ expression, Rac1 phosphorylation, and cancer invasion.