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Degradation of helicase-like transcription factor (HLTF) by β-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis
Ye Tan1,2,† , Di Wu1,† , Ze-Yu Liu1,† , Hong-Qiang Yu1,† , Xiang-Ru Zheng2,† , Xiao-Tong Lin1 , Ping Bie2 , Lei-Da Zhang1 , Chuan-Ming Xie1,*
1Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
2Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing 401120, China
These authors contributed equally to this work
*Correspondence to:Chuan-Ming Xie ,
J Mol Cell Biol, Volume 15, Issue 2, February 2023, mjad012,
Keyword: HLTF, β-TrCP, mTOR, ubiquitination, hepatocellular carcinoma, cell proliferation, metastasis

Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumour suppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, we observed that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with the survival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR) activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked β-TrCP overexpression- or HLTF knockdown-mediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlated with elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCC cell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that the β-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potential therapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis.