MYC-STAMBPL1-TOE1 正反馈环路介导肝细胞癌中 EGFR 的稳定性。
A MYC-STAMBPL1-TOE1 positive feedback loop mediates EGFR stability in hepatocellular carcinoma.
机构信息
State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, P.R. China.
Department of Clinical Pathology, Nanyang Central Hospital, Nanyang, P.R. China.
出版信息
Cell Rep. 2024 Oct 22;43(10):114812. doi: 10.1016/j.celrep.2024.114812. Epub 2024 Oct 9.
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.
STAM 结合蛋白样 1（STAMBPL1）是一种赖氨酸 63 特异性连接的去泛素化酶，其在肝细胞癌中的作用仍不清楚。在这里，我们报告了 STAMBPL1 在调节表皮生长因子受体（EGFR）的蛋白和 mRNA 稳定性方面的功能。STAMBPL1 缺陷可减弱体外和体内的肝肿瘤发生。STAMBPL1 从 EGFR 上去除 K63 连接的泛素链，以避免 EGF 刺激时溶酶体降解。STAMBPL1 通过激活 EGFR1 蛋白 1（TOE1）上靶标的 K63 连接的泛素链的切割，增强 EGFR 的 RNA 有效剪接，以避免内含子保留。此外，EGFR-MYC 轴对 STAMBPL1 的转录具有正反馈调节作用，体内耗尽 STAMBPL1 可削弱 MYC 驱动的肝肿瘤发生。STAMBPL1 或 TOE1 的抑制作用协同增强仑伐替尼的抗肿瘤活性。我们的工作展示了 STAMBPL1 在肝癌中的作用机制，并提示其作为肝癌治疗的潜在治疗靶点。
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