2. Academic Validation
  3. A MYC-STAMBPL1-TOE1 positive feedback loop mediates EGFR stability in hepatocellular carcinoma

A MYC-STAMBPL1-TOE1 positive feedback loop mediates EGFR stability in hepatocellular carcinoma

  • Cell Rep. 2024 Oct 22;43(10):114812. doi: 10.1016/j.celrep.2024.114812.
Hongli Zhang 1,  Zixuan Wang 1,  Jian Zhang 2,  Zhengtai Li 1,  Jiaxuan Liu 1,  Jingwen Yu 3,  Yiqi Zhao 3,  Fan Guo 4,  Wei-Dong Chen 5,  Yan-Dong Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, P.R. China.
  • 2 Department of Clinical Pathology, Nanyang Central Hospital, Nanyang, P.R. China.
  • 3 State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, P.R. China; Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P. R. China.
  • 4 Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P. R. China.
  • 5 Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P. R. China; Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, The People's Hospital of Hebi, School of Medicine, Henan University, Henan, P.R. China. Electronic address: wdchen666@163.com.
  • 6 State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, P.R. China. Electronic address: ydwangbuct2009@163.com.
PMID: 39388352 DOI: 10.1016/j.celrep.2024.114812
Abstract

The role of STAM binding protein-like 1 (STAMBPL1), a Lys-63 linkage-specific Deubiquitinase, in hepatocellular carcinoma has remained elusive. Here, we report the functions of STAMBPL1 in modulating the stability of the protein and mRNA of the epidermal growth factor receptor (EGFR). STAMBPL1 deficiency attenuates liver tumorigenesis in vitro and in vivo. STAMBPL1 removes K63-linked ubiquitin chains from EGFR to avoid lysosome degradation upon EGF stimulation. STAMBPL1 augments RNA efficient splicing of EGFR to avoid intron retention by activating cleavage of the K63-linked ubiquitin chain on the target of EGR1 protein 1 (TOE1). Moreover, the EGFR-MYC axis has a positive feedback regulation on the transcription of STAMBPL1, and depletion of STAMBPL1 in vivo blunts MYC-driven liver tumorigenesis. Inhibition of STAMBPL1 or TOE1 synergistically improves the antitumor activity of lenvatinib. Our work shows the mechanism of STAMBPL1 in liver Cancer and suggests it as a potential therapeutic target for liver Cancer treatment.

Keywords

CP: Cancer; EGFR; Hepatocellular carcinoma; MYC; RNA splicing; STAMBPL1; TOE1; deubiquitination.

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