Overexpression of ubiquitin-conjugating enzyme E2 L3 in hepatocellular carcinoma potentiates apoptosis evasion by inhibiting the GSK3β/p65 pathway

• Published in: Cancer letters 2020-07, Vol.481, p.1-14
• Main Authors: Tao, Na-Na, Zhang, Zhen-Zhen, Ren, Ji-Hua, Zhang, Juan, Zhou, Yu-Jiao, Wai Wong, Vincent Kam, Kwan Law, Betty Yuen, Cheng, Sheng-Tao, Zhou, Hong-Zhong, Chen, Wei-Xian, Xu, Hong-Mei, Chen, Juan
• Format: Article
• Language: English
• Subjects: Amino acids; Animal models; Animals; Antibodies; Antigens; Apoptosis; Apoptosis - genetics; BAX protein; BIM protein; Carcinogenesis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Enzymes; Glycogen Synthase Kinase 3 beta - genetics; GSK3β; Hepatocellular carcinoma; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nuclear transport; Phosphorylation - genetics; Plasmids; Proteins; Signal Transduction - genetics; Therapeutic applications; Transcription Factor RelA - genetics; Tumors; UBE2L3; Ubiquitin; Ubiquitin-conjugating enzyme; Ubiquitin-Conjugating Enzymes - genetics; Up-Regulation - genetics
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.03.028

UBE2L3 is a ubiquitin-conjugating protein belonging to the E2 family that consists of 153 amino acid residues. In this study, we found that UBE2L3 was generally upregulated in clinical HCC samples compared to non-tumour samples and that there was a strong association between high UBE2L3 expression and tumour size, clinical grade and prognosis in HCC patients. UBE2L3 depletion inhibited the proliferation and induced the apoptosis of HCC cells. At the molecular level, we observed that UBE2L3 depletion enhanced the protein stability of GSK3β, thus promoting the expression and activation of GSK3β. Subsequently, activated GSK3β phosphorylated p65 and promoted its nuclear translocation to increase the expression of target genes, including PUMA, Bax, Bim, Bad, and Bid. In vivo, knockout of UBE2L3 in HCC cells inhibited tumour growth in orthotopic liver injection nude mouse models. Moreover, inhibition of p65 or GSK3β significantly restored the effects induced by UBE2L3 knockout in HCC. Together, this study reveals the stimulatory effect of UBE2L3 on HCC cell proliferation, suggesting that UBE2L3 may be an important pro-tumorigenic factor in liver carcinogenesis and a potential therapeutic target of HCC. •We found that UBE2L3 was frequently up-regulated in clinical HCC samples, which was associated with poor prognosis.•UBE2L3 depletion inhibited cell proliferation and promoted cell apoptosis by through promoting GSK3β/p65 pathway.•UBE2L3 overexpression decreased the protein stability of GSK3β via ubiquitin-mediated proteasome degradation.