2. Academic Validation
  3. TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma

TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma

  • Cell Death Dis. 2025 Jun 5;16(1):438. doi: 10.1038/s41419-025-07745-3.
Jing He # 1 2,  Mingen Lin # 2,  Fei Teng # 3,  Xue Sun 2,  Ziyin Tian 2,  Jiaxi Li 2,  Yan Ma 2,  Yue Dai 2,  Yi Gao 2,  Hongchen Li 1,  Tongguan Tian 1,  Kai Xu 4,  Xinxing Li 5,  Lei Lv 6,  Yanping Xu 7
Affiliations

Affiliations

  • 1 Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 2 MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 3 Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 4 Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. kaikai607@hotmail.com.
  • 5 Department of Gastrointestinal Surgery, Tongji Hospital Medical College of Tongji University, Shanghai, China. ahtxxxx2015@163.com.
  • 6 MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. lvlei@fudan.edu.cn.
  • 7 Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. yanpingxu@tongji.edu.cn.
  • # Contributed equally.
PMID: 40473594 DOI: 10.1038/s41419-025-07745-3
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of global cancer-associated mortality. Although various therapies have substantially ameliorated clinical outcome, patients invariably suffer from Cancer relapse, highlighting the need for more optimized therapeutic strategies. Here, we report that deficiency of DNA methylcytosine dioxygenase TET2 sensitizes HCC cells to sorafenib and verteporfin treatments. Mechanistically, knockout of TET2 enhances the dephosphorylation of YAP Ser127, thus promoting its activity. RNA-seq analysis reveals that MC1R, a GPCR, is strikingly decreased upon TET2 deficiency. Furthermore, TET2 catalyzes demethylation of MC1R promoter to stimulate its transcription. MC1R subsequently boosts cAMP-PKA signaling to phosphorylate YAP Ser127 in both ligand dependent and independent manners. Importantly, deletion of MC1R accelerates tumor growth of HCC, which is reversed by the treatment of YAP-TEAD complex inhibitor verteporfin. Synergistic combination of MC1R expression driver vitamin C and its ligand α-MSH dramatically represses HCC growth. Notably, TET2-MC1R-YAP axis is evidenced in HCC specimens and plays a vital role in prognosis of HCC. Collectively, these findings not only elucidate a previously unidentified epigenetic regulatory mechanism of MC1R transcription and underscore the functional significance of MC1R signaling in tumorigenesis of HCC, but also provide potential targets and clinical strategies for HCC therapy.

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