MARCH5 promotes autophagy through interaction with P62 leading to malignant progression of hepatocellular carcinoma

Dysregulated MARCH5 expression and impaired autophagy have been reported separately in some cancers. However, their relationship has not been explored in hepatocellular carcinoma (HCC). Here, we present evidence that MARCH5 promotes autophagy by interacting with p62 to mediate its ubiquitylation for subsequent degradation and thus contributes to cancer proliferation, invasion, and migratory migration. Our clinical data showed that MARCH5 was overexpressed in HCC patients and patients with high MARCH5 expression had poorer prognosis and higher recurrence rate after tumor resection. In addition, we found that overexpression of MARCH5 significantly promoted tumor cell growth and EMT-mediated invasion and migration of HCC cells, while knockdown of MARCH5 suppressed the malignant phenotype of tumor cells. Moreover, overexpression of MARCH5 significantly induced autophagy and increased autophagic flux. Mechanistically, MARCH5 was negatively correlated with P62 expression at the protein level rather than at transcriptional level, and MARCH5 induced autophagy through promoting the degradation of p62 induced by ubiquitination modification demonstrating by shortened the half-life of p62, which contributed to the malignant progression of HCC.