LAMTOR5 promotes hepatoma growth in mice by disrupting LC3-p62-mediated autophagy and preventing p62 proteasome degradation.

In the etiology of cancer, p62 is a well-known autophagic receptor and signaling adapter. High p62 expression is known to accelerate hepatocellular carcinoma (HCC) growth by activating various downstream signaling pathways. In this study, we investigated the activity of elevated p62 and its associated regulatory mechanisms during HCC progression. By conducting immunohistochemical staining on a human liver tissue microarray including 10 liver cancer tissues and 10 paracancerous tissues, we found that the expression levels of p62 and oncoprotein LAMTOR5 were markedly increased in HCC tissues compared with noncancerous tissues; LAMTOR5 was positively associated with p62 expression, and high LAMTOR5 or p62 expression predicted reduced overall and release-free survival. Transcriptomic analysis revealed that LAMTOR5 overexpression inhibited autophagy in HepG2 cells. We demonstrated that LAMTOR5 interacted with the LC3-interacting region domain of p62 and inhibited autophagy caused by the binding of p62 to LC3, thereby leading to the accumulation of p62 protein in HCC. Moreover, LAMTOR5 blocked p62 ubiquitination-mediated proteasome degradation, which increased the stability of p62. Functionally, p62 overexpression reversed LAMTOR5 deficiency-reduced hepatoma cell proliferation in vitro and in vivo. Lenvatinib, a multi-receptor tyrosine kinase inhibitor, significantly suppressed HCC growth in vitro and in vivo by downregulating LAMTOR5 and p62 expression. We conclude that LAMTOR5-mediated p62 stabilization is a novel HCC growth mechanism, targeting this axis as a promising therapeutic strategy.