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Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma

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Abstract

Cholesterol biosynthesis plays a critical role in rapidly proliferating tumor cells. X-box binding protein 1 (XBP1), which was first characterized as a basic leucine zipper-type transcription factor, exists in an unspliced (XBP1-u) and spliced (XBP1-s) form. Recent studies showed that unspliced XBP1 (XBP1-u) has unique biological functions independent from XBP1-s and could promote tumorigenesis; however, whether it is involved in tumor metabolic reprogramming remains unknown. Herein, we found that XBP1-u promotes tumor growth by enhancing cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells. Specifically, XBP1-u colocalizes with sterol regulatory element-binding protein 2 (SREBP2) and inhibits its ubiquitination/proteasomal degradation. The ensuing stabilization of SREBP2 activates the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. We subsequently show that the XBP1-u/SREBP2/HMGCR axis is crucial for enhancing cholesterol biosynthesis and lipid accumulation as well as tumorigenesis in HCC cells. Taken together, these findings reveal a novel function of XBP1-u in promoting tumorigenesis through increased cholesterol biosynthesis in hepatocarcinoma cells. Hence, XBP1-u might be a potential target for anti-tumor therapeutic strategies that focus on cholesterol metabolism in HCC.

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Acknowledgements

The authors thank Professor Xia Zhang (Institute of Pathology, Southwest Hospital, Third Military Medical University) for his helpful comments in preparing this manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China No. 31871367 (V. Kasim), No. 32070715 (V. Kasim), No. 81872273 (S. Wu), and No. 82173029 (S. Wu).

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Author notes

  1. Mankun Wei, Uli Nurjanah and Arin Herkilini contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, 174 Shazheng Street, Shapingba, Chongqing, 400044, China

    Mankun Wei, Uli Nurjanah, Arin Herkilini, Yanjun Li, Shourong Wu & Vivi Kasim

  2. The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Mankun Wei, Uli Nurjanah, Arin Herkilini, Yanjun Li, Shourong Wu & Vivi Kasim

  3. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui, China

    Can Huang

  4. Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, 305-8566, Japan

    Makoto Miyagishi

  5. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China

    Shourong Wu & Vivi Kasim

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  1. Mankun Wei
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Contributions

VK and SW conceived the project, designed the experiments, analyzed and interpreted the experimental results, and wrote the manuscript; MW, UN, AH performed most of the experiments and analyzed the experimental data; CH and YL carried out part of the experiments, constructed the vectors and interpreted the data; MM designed the shRNA target sequences and provided part of experimental materials for vector constructions.

Corresponding authors

Correspondence to Shourong Wu or Vivi Kasim.

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Our studies did not include human participants, human data or human tissue. For the animal studies, a protocol detailing experimental procedures following the Animal Care and Use Committee of the Chongqing University Cancer Hospital guidelines was submitted to—and approved by—the Laboratory Animal Welfare and Ethics Committee of Chongqing University Cancer Hospital.

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Wei, M., Nurjanah, U., Herkilini, A. et al. Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma. Cell. Mol. Life Sci. 79, 472 (2022). https://doi.org/10.1007/s00018-022-04504-x

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