Degradation of helicase-like transcription factor(HLTF)byβ-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis  

作　　者：Ye Tan Di Wu Ze-Yu Liu Hong-Qiang Yu Xiang-Ru Zheng Xiao-Tong Lin Ping Bie Lei-Da Zhang Chuan-Ming Xie 

机构地区：[1]Key Laboratory of Hepatobiliary and Pancreatic Surgery,Institute of Hepatobiliary Surgery,Southwest Hospital,Third Military Medical University(Army Medical University),Chongqing 400038,China [2]Department of Hepatobiliary and Pancreatic Surgery,The Third Affiliated Hospital of Chongqing Medical University(Gener Hospital),Chongqing 401120,China

出　　处：《Journal of Molecular Cell Biology》2023年第2期29-42,共14页分子细胞生物学报（英文版）

基　　金：supported by the Introduction of Special Funds for Talents from the Third Military Medical University(Army Medical University,4174C6)to C.-M.X.

摘　　要：Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumoursuppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, weobserved that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with thesurvival 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 knockdownmediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlatedwith elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCCcell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that theβ-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potentialtherapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis.

关 键 词：HLTF β-TrCP MTOR UBIQUITINATION hepatocellular carcinoma cell proliferation metastasis 

分 类 号：R735.7[医药卫生—肿瘤]