Abstract
Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of β-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.
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Data availability
The RNA-seq and ChIP-seq data is archived in the GEO database (GSE164615) and available to all. Other data that support the findings of this study is available from the corresponding author upon request.
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Funding
This study was supported by National Key R&D Program of China (2022YFA0807000) and Chinese Civil-Military Integration Program (145BGQ090003060X) to XS, the Fundamental Research Funds for the Central Universities (YCJJ202201011) to TZ, Young and Middle-aged Discipline Leader of Henan Provincial Health Commission (HNSWJW-2020027) and Excellent Young Scholar Fund of Natural Science Foundation of Henan Province (222300420072) to YZ, National Natural Science Foundation of China (81972752) to YJ, and Hepatobiliary Research Foundation of Henan Digestive Disease Association (GDXZ2019004) to JHS.
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TZ performed most of the experiments and helped in writing the manuscript. FZ performed bioinformatics analysis and helped in writing the manuscript. YZ helped in designing the study, constructed the TMA, and revised the manuscript. FC and WM contributed to experiments and data analyses. KW helped in TMA analyses. CX provided mouse HCC materials. QZ provided the MKC8866 compound. JHS, RZ, NL, YL, and YJ helped in data analyses and revised the manuscript. XS conceived the project, supervised the work, and wrote the manuscript. All authors contributed to the article and approved the submitted version.
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QZ is a shareholder of Fosun Orinove. Other authors declare no competing interests.
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Zhang, T., Zhao, F., Zhang, Y. et al. Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling. Oncogene 43, 1233–1248 (2024). https://doi.org/10.1038/s41388-024-02988-4
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DOI: https://doi.org/10.1038/s41388-024-02988-4