Cell Death and Disease (Feb 2023)

Loss of 5-hydroxymethylcytosine induces chemotherapy resistance in hepatocellular carcinoma via the 5-hmC/PCAF/AKT axis

  • Xiao-Jun Guo,
  • Xiao-Yong Huang,
  • Xuan Yang,
  • Jia-Cheng Lu,
  • Chuan-Yuan Wei,
  • Chao Gao,
  • Yan-Zi Pei,
  • Yi Chen,
  • Qi-Man Sun,
  • Jia-Bin Cai,
  • Jian Zhou,
  • Jia Fan,
  • Ai-Wu Ke,
  • Yujiang G. Shi,
  • Ying-Hao Shen,
  • Peng-Fei Zhang,
  • Guo-Ming Shi,
  • Guo-Huan Yang

Journal volume & issue
Vol. 14, no. 2
pp. 1 – 13


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Abstract Multidrug resistance is a major challenge in treating advanced hepatocellular carcinoma (HCC). Although recent studies have reported that the multidrug resistance phenotype is associated with abnormal DNA methylation in cancer cells, the epigenetic mechanism underlying multidrug resistance remains unknown. Here, we reported that the level of 5-hydroxymethylcytosine (5-hmC) in human HCC tissues was significantly lower than that in adjacent liver tissues, and reduced 5-hmC significantly correlated with malignant phenotypes, including poor differentiation and microvascular invasion; additionally, loss of 5-hmC was related to chemotherapy resistance in post-transplantation HCC patients. Further, the 5-hmC level was regulated by ten-eleven translocation 2 (TET2), and the reduction of TET2 in HCC contributes to chemotherapy resistance through histone acetyltransferase P300/CBP-associated factor (PCAF) inhibition and AKT signaling hyperactivation. In conclusion, loss of 5-hmC induces chemotherapy resistance through PCAF/AKT axis and is a promising chemosensitivity prediction biomarker and therapeutic target for HCC patients.