Tmub1 Suppresses Hepatocellular Carcinoma By Promoting The Ubiquitination Of Delta Np63 Isoforms

Transmembrane and ubiquitin-like domain-containing 1 (Tmub1) inhibits hepatocyte proliferation during liver regeneration, but its role in hepatocellular carcinoma (HCC) has yet to be revealed. In this study, we show that the levels of Tmubl were significantly lower in HCC tissues and cells than they were in adjacent tissues and normal hepatic cells, and the low levels of Tmub1 indicated a poor prognosis in HCC patients. Xenograft growth assay revealed that Tmub1 represses HCC growth in vivo. In addition, Tmubl formed a protein complex with apoptosis-associated protein tumor protein 63 (p63), especially with the Delta N isoforms (Delta Np63 alpha, beta, and gamma). Further loss- and gain-of-function analyses indicated that Tmubl promotes apoptosis of Hep3B and MHCC-LM3 cells. Tmub1 decreased the protein expression of Delta Np63, and the pro-apoptotic effect of Tmub1 can be reversed by Delta Np63 isoforms (alpha, beta, and gamma). Additionally, we report that Tmub1 promotes the ubiquitination and degradation of Delta Np63 proteins. Finally, we confirmed in HCC tissues that Tmub1 is negatively correlated with Delta Np63 and positively correlated with the level of apoptosis. Taken together, Tmub1 suppresses HCC by enhancing the ubiquitination and degradation of Delta Np63 isoforms to induce HCC cell apoptosis. These findings provide a potential strategy for the management of HCC.