Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt
Tingting Zhang1, Faming Zhao1, Yi Zhang2,3
1Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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.
Insights
The IRE1α-XBP1s pathway is crucial for hepatocellular carcinoma (HCC) cell survival. Inhibiting this pathway offers a potential therapeutic strategy for HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- The role of IRE1α (also known as ERN1) in human hepatocellular carcinoma (HCC) is not fully understood.
- Previous studies in mice suggest liver-specific Ern1 knockout impairs HCC tumor progression.
Purpose of the Study:
- To elucidate the mechanistic role of the IRE1α-XBP1s pathway in human HCC.
- To investigate XBP1s as a potential therapeutic target in HCC.
Main Methods:
- Investigated XBP1s' role in HCC cell survival in vitro and in vivo.
- Examined the interaction between XBP1s and LEF1, a β-catenin co-factor.
- Utilized IRE1α inhibitors to assess therapeutic efficacy on tumor explants and xenografts.
- Employed machine learning to develop a prognostic signature based on XBP1s/LEF1 activity.
Main Results:
- XBP1s, the effector of IRE1α, is essential for HCC cell survival.
- XBP1s directly transactivates LEF1 and forms a complex enhancing Wnt signaling.
- XBP1s and LEF1 activities correlate with human HCC progression and prognosis.
- IRE1α inhibition reduced tumor viability and growth in patient-derived xenografts.
Conclusions:
- The IRE1α-XBP1s pathway plays a key mechanistic role in human HCC.
- Targeting the IRE1α-XBP1s axis presents a promising therapeutic approach for HCC with activated Wnt/LEF1 signaling.
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