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 Tmub1 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, Tmub1 formed a protein complex with apoptosis-associated protein tumor protein 63 (p63), especially with the ΔN isoforms (ΔNp63α, β, and γ). Further loss- and gain-of-function analyses indicated that Tmub1 promotes apoptosis of Hep3B and MHCC-LM3 cells. Tmub1 decreased the protein expression of ΔNp63, and the pro-apoptotic effect of Tmub1 can be reversed by ΔNp63 isoforms (α, β, and γ). Additionally, we report that Tmub1 promotes the ubiquitination and degradation of ΔNp63 proteins. Finally, we confirmed in HCC tissues that Tmub1 is negatively correlated with ΔNp63 and positively correlated with the level of apoptosis. Taken together, Tmub1 suppresses HCC by enhancing the ubiquitination and degradation of ΔNp63 isoforms to induce HCC cell apoptosis. These findings provide a potential strategy for the management of HCC.

跨膜和泛素样结构域1（Tmub1）抑制肝再生过程中肝细胞增殖，但其在肝细胞癌（HCC）中的作用尚未揭示。在这项研究中，我们显示肝癌组织和细胞中Tmub1的水平显着低于邻近组织和正常肝细胞中的水平，而Tmub1的低水平表明HCC患者的预后较差。异种移植生长测定显示Tmub1抑制体内HCC生长。此外，Tmub1与凋亡相关蛋白肿瘤蛋白63（p63），尤其是与ΔN同工型（ΔNp63α，β和γ）形成了蛋白复合物。进一步的功能丧失和获得功能分析表明，Tmub1促进Hep3B和MHCC-LM3细胞凋亡。Tmub1降低了ΔNp63的蛋白表达，并且Tmub1的促凋亡作用可以被ΔNp63亚型（α，β和γ）逆转。此外，我们报告Tmub1促进ΔNp63蛋白的泛素化和降解。最后，我们在肝癌组织中证实Tmub1与ΔNp63呈负相关，与凋亡水平呈正相关。两者合计，Tmub1通过增强ΔNp63亚型的泛素化和降解来诱导HCC细胞凋亡来抑制HCC。这些发现为肝癌的管理提供了潜在的策略。