UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

The ubiquitin-conjugating enzyme (E2) is a critical component of the ubiquitin-proteasome system and regulates hepatocarcinogenesis by controlling protein degradation. Ubiquitin-conjugating enzyme E2 O (UBE2O), a member of the E2 family, functions as an oncogene in human cancers. Nevertheless, the role of UBE2O in hepatocellular carcinoma (HCC) remains unknown yet. Here, we demonstrated that the UBE2O level was markedly upregulated in HCC compared with adjacent noncancerous tissues. UBE2O overexpression was also confirmed in HCC cell lines. UBE2O overexpression was prominently associated with advanced tumor stage, high tumor grade, venous infiltration, and reduced HCC patients' survivals. UBE2O knockdown inhibited the migration, invasion, and proliferation of HCCLM3 cells. UBE2O overexpression enhanced the proliferation and mobility of Huh7 cells. Mechanistically, UBE2O mediated the ubiquitination and degradation of AMP-activated protein kinase alpha 2 (AMPK alpha 2) in HCC cells. UBE2O silencing prominently increased AMPK alpha 2 level and reduced phosphorylated mechanistic target of rapamycin kinase (p-mTOR), MYC, Cyclin D1, HIF1 alpha, and SREBP1 levels in HCCLM3 cells. UBE2O depletion markedly activated the AMPK alpha 2/mTOR pathway in Huh7 cells. Moreover, AMPK alpha 2 silencing reversed UBE2O downregulation-induced mTOR pathway inactivation. Rapamycin, an inhibitor of mTOR, remarkably abolished UBE2O-induced mTOR phosphorylation and HCC cell proliferation and mobility. To conclude, UBE2O was highly expressed in HCC and its overexpression conferred to the poor clinical outcomes of patients. UBE2O contributed to the malignant behaviors of HCC cells, including cell proliferation, migration, and invasion, by reducing AMPK alpha 2 stability and activating the mTOR pathway.

Automated summary

The study revealed that UBE2O was significantly upregulated in HCC and associated with tumor progression and poor clinical outcomes. UBE2O promoted malignant behaviors of HCC cells by reducing AMPKα2 stability and activating the mTOR pathway.