Molecular mechanism of WWP1‐mediated ubiquitination modification affecting proliferation and invasion/migration of liver cancer cells

Abstract

Liver cancer is the most prevalent fatal malignancy across the globe. The present study aims to explore the molecular mechanism of E3 ligase WWP1 in liver cancer cell proliferation and invasion/migration. RT‐qPCR and Western blot were performed to detect WWP1, KLF14, and VEPH1 expressions in liver cancer cell lines. Furthermore, WWP1 expression was silenced in cells, followed by the detection of cell viability, proliferation, and invasion/migration by CCK‐8, colony formation, and Transwell assays, respectively. ChIP was used to analyze the binding relationship between WWP1 and KLF14. We measured the KLF14 ubiquitination level and KLF14 enrichment on the VEPH1 promoter after MG132 treatment. Dual‐luciferase reporter assay was used to validate the binding relationship between KLF14 and VEPH1. Consequently, WWP1 was highly expressed in liver cancer cells; WWP1 silencing reduced the proliferation and invasion/migration of liver cancer cells. Mechanistically, WWP1 promoted KLF14 ubiquitination degradation; KLF14 was enriched on the VEPH1 promoter to promote its transcription and protein expression. Inhibiting KLF14 or VEPH1 partially minimized the inhibitory effect of WWP1 silencing on liver cancer cell proliferation and invasion/migration. In summary, WWP1 degrades KLF14 through ubiquitination, hence repressing VEPH1 expression and accelerating proliferation and invasion/migration of liver cancer cells.