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.
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