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

作者全名："Tan, Ye; Wu, Di; Liu, Ze-Yu; Yu, Hong-Qiang; Zheng, Xiang-Ru; Lin, Xiao-Tong; Bie, Ping; Zhang, Lei-Da; Xie, Chuan-Ming"

作者地址："[Tan, Ye; Wu, Di; Liu, Ze-Yu; Yu, Hong-Qiang; Lin, Xiao-Tong; Zhang, Lei-Da; Xie, Chuan-Ming] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Key Lab Hepatobiliary & Pancreat Surg,Inst Hepatob, Chongqing 400038, Peoples R China; [Tan, Ye; Zheng, Xiang-Ru; Bie, Ping] Chongqing Med Univ, Dept Hepatobiliary & Pancreat Surg, Affiliated Hosp 3, Gen Hosp, Chongqing 401120, Peoples R China"

通信作者："Xie, CM (通讯作者)，Third Mil Med Univ, Army Med Univ, Southwest Hosp, Key Lab Hepatobiliary & Pancreat Surg,Inst Hepatob, Chongqing 400038, Peoples R China."

来源：JOURNAL OF MOLECULAR CELL BIOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001116274800001

JCR分区：Q2

影响因子：5.3

年份：2023

卷号：15

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：HLTF; beta-TrCP; mTOR; ubiquitination; hepatocellular carcinoma; cell proliferation; metastasis

摘要："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 beta-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 beta-TrCP overexpression- or HLTF knockdown-mediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlated with elevated expression of beta-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 beta-TrCP, indicating that the beta-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 beta-TrCP/HLTF/p62/mTOR axis."

基金机构：Third Military Medical University; [4174C6]

基金资助正文："This work was supported by the Introduction of Special Funds for Talents from the Third Military Medical University (Army Medical University, 4174C6) to C.-M.X."