The E3 ligase HUWE1 mediates TGFBR2 ubiquitination and promotes gastric cancer cell proliferation, migration, and invasion.

Abstract

HUWE1, as a well-known E3 ligase, has an oncogenic or tumor-suppressive role in various cancers by mediating ubiquitination and degradation of substrates. However, the role and actionmechanism of HUWE1 in gastric cancer (GC) remain unclear. This study aimed to investigate whether HUWE1 plays a role in GC development in vitro by mediating transforming growth factor-β receptor 2 (TGFBR2) ubiquitination and degradation. HUWE1 was overexpressed in SGCA-7901 GC cells and silenced in MGC-803 GC cells. Then, GC cell proliferation, migration, and invasion were evaluated by MTT assay and Transwell migration and invasion assay, respectively. The regulatory effect and mechanism of HUWE1 on TGFBR2 expression were assessed by qRT-PCR, western blot, and ubiquitination assay. HUWE1 mRNA and protein levels were higher in human GC tissues than in matched noncancerous gastric tissues. HUWE1 overexpression promoted, whereas HUWE1 silencing inhibited GC cell proliferation, migration, and invasion. HUWE1 promoted ubiquitination and degradation of TGFBR2. TGFBR2 overexpression impaired the tumor-promoting effect of HUWE1 overexpression in regulating GC cell behaviors. HUWE1 promoted GC cell proliferation, migration, and invasion, at least partially, by mediating TGFBR2 ubiquitination. Our data indicated a novel regulatory mechanism of HUWE1 in GC development, and provided a potential idea for the disease treatment.