Journal of cancer research and clinical oncology · 2025
FBXW11 inhibits tumorigenesis by ubiquitinating YB1 in hepatocarcinoma.
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Liu Wuguang, Xu Bin, Wang Tong, Liu Xiaolong, Dong Chengyong, Wang Liming
Аннотация
PURPOSE: The study aimed to investigate the role of FBXW11 in hepatocellular carcinoma (HCC) and its underlying mechanism. Specifically, we explored whether FBXW11 inhibits tumorigenesis by regulating YB1 ubiquitination and elucidated the functional significance of the FBXW11-YB1 axis in HCC progression.
METHODS: Clinical HCC specimens and cell lines (HCC-LM3, HuH7, Hep3B, SNU-449) were used. FBXW11 and YB1 expression were analyzed via Western blotting and immunohistochemistry (IHC). Gain- and loss-of-function assays (FBXW11 overexpression/knockdown) were performed to assess cell proliferation. Co-immunoprecipitation (Co-IP), mass spectrometry, and ubiquitination assays identified protein interactions and ubiquitination patterns. In vivo tumorigenesis was evaluated using xenograft models in nude mice. Correlations with clinicopathological features and survival were analyzed via statistical methods.
RESULTS: FBXW11 was significantly downregulated in HCC tissues, correlated with advanced TNM stages and poor overall survival (HR = 3.058, P = 0.042). FBXW11 overexpression suppressed HCC cell proliferation, while knockdown enhanced it. Mechanistically, FBXW11 directly interacted with the cold shock domain (CSD) of YB1, promoting K48-linked polyubiquitination and proteasomal degradation of YB1. YB1 overexpression rescued the tumor-suppressive effects of FBXW11 overexpression. In vivo, FBXW11 overexpression inhibited tumor growth by suppressing the YB1/Akt/mTOR signaling pathway, which was rescued by YB1 re-expression.
CONCLUSION: FBXW11 acts as a tumor suppressor in HCC by mediating YB1 ubiquitination and degradation, thereby inhibiting the Akt/mTOR pathway. The FBXW11-YB1 axis represents a novel regulatory mechanism in hepatocarcinogenesis, highlighting FBXW11 as a potential prognostic biomarker and therapeutic target for HCC.
METHODS: Clinical HCC specimens and cell lines (HCC-LM3, HuH7, Hep3B, SNU-449) were used. FBXW11 and YB1 expression were analyzed via Western blotting and immunohistochemistry (IHC). Gain- and loss-of-function assays (FBXW11 overexpression/knockdown) were performed to assess cell proliferation. Co-immunoprecipitation (Co-IP), mass spectrometry, and ubiquitination assays identified protein interactions and ubiquitination patterns. In vivo tumorigenesis was evaluated using xenograft models in nude mice. Correlations with clinicopathological features and survival were analyzed via statistical methods.
RESULTS: FBXW11 was significantly downregulated in HCC tissues, correlated with advanced TNM stages and poor overall survival (HR = 3.058, P = 0.042). FBXW11 overexpression suppressed HCC cell proliferation, while knockdown enhanced it. Mechanistically, FBXW11 directly interacted with the cold shock domain (CSD) of YB1, promoting K48-linked polyubiquitination and proteasomal degradation of YB1. YB1 overexpression rescued the tumor-suppressive effects of FBXW11 overexpression. In vivo, FBXW11 overexpression inhibited tumor growth by suppressing the YB1/Akt/mTOR signaling pathway, which was rescued by YB1 re-expression.
CONCLUSION: FBXW11 acts as a tumor suppressor in HCC by mediating YB1 ubiquitination and degradation, thereby inhibiting the Akt/mTOR pathway. The FBXW11-YB1 axis represents a novel regulatory mechanism in hepatocarcinogenesis, highlighting FBXW11 as a potential prognostic biomarker and therapeutic target for HCC.