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Hypoxia-activated XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of ΔNp63α expression and promote breast cancer metastasis independent of HIF1α

Cell Death & Differentiation volume 31, pages 447–459 (2024)Cite this article

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Abstract

Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α in a HIF1α-independent manner. We show that hypoxia-activated XBP1s forms a stable repressor protein complex with HDAC2 and EZH2 to suppress ΔNp63α transcription. Notably, H3K27ac is predominantly occupied on the ΔNp63 promoter under normoxia, while H3K27me3 on the promoter under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the switch of H3K27ac to H3K27me3. Pharmacological inhibition or the knockdown of either HDAC2 or EZH2 leads to increased H3K27ac, accompanied by the reduced H3K27me3 and restoration of ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Furthermore, the pharmacological inhibition of IRE1α, but not HIF1α, upregulates ΔNp63α expression in vitro and inhibits tumor metastasis in vivo. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecular basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.

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Fig. 1: Hypoxia inhibits ΔNp63α expression via EZH2-mediated upregulation of H3K27me3 in promoting cell motility in a HIF1α-independent manner.
Fig. 2: Hypoxia activates XBP1s to inhibit ΔNp63α expression in promoting cell invasion by EZH2.
Fig. 3: Hypoxia downregulates H3K27ac and upregulates H3K27me3 via XBP1s-HDAC2 axis in promoting cell migration.
Fig. 4: Hypoxia facilitates XBP1s interaction with the HDAC2-EZH2 complexes and loading on the ΔNp63 promoter resulting in switching H3K27ac to H3K27me3 to inhibit ΔNp63 transcription.
Fig. 5: XBP1s inhibits ΔNp63a expression to promote cell migration and tumor metastasis.
Fig. 6: Expression of TP63 is negatively correlated with XBP1/HDAC2/EZH2 in human breast cancer.

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The data analyzed during this study are included in this published article and the supplemental data files.

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Acknowledgements

We are grateful for members of Xiao lab for stimulating discussion during this study.

Funding

This work was supported in part by National Natural Science Foundation of China (NSFC) (81903018, 92259102), National Key R&D Program of China (2022YFA1103700), Natural Science Foundation of Chengdu Medical College (CYZZD21-01), Introduction Foundation of High-level Talents of The First Affiliated Hospital of Chengdu Medical College (CYFY-GQ37) and Disciplinary Construction Innovation Team Foundation of Chengdu Medical College (CMCXK-2101).

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Authors and Affiliations

  1. School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China

    Hu Chen, Ruidong Ma & Liyuan Deng

  2. Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China

    Shuhan Yu, Yong Yi & Mengmeng Niu

  3. Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Chuan Xu & Zhi-Xiong Jim Xiao

  4. Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China

    Zhi-Xiong Jim Xiao

  5. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Zhi-Xiong Jim Xiao

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Contributions

HC and SHY performed all the biochemical experiments. SHY, RDM, and LYD analyzed and processed the IHC data from cell lines. YY and MMN analyzed and processed the public database. HC, CX and ZXX analyzed all experiments, managed the overall study, and supervised manuscript preparation and submission. All authors have contributed to the final version of the manuscript and rebuttal.

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Correspondence to Hu Chen, Chuan Xu or Zhi-Xiong Jim Xiao.

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All human tissue research in this study had the approval of ethics committees of the Affiliated Taizhou People’s Hospital of Nanjing Medical University (Taizhou, China) and Shanghai Outdo Biotech (Shanghai, China). All participants provided informed consent. Animal care and experiments in this study were approved by the Institutional Animal Care and Use Committee (IACUC) of Chengdu Medical College, and the procedures were carried out according to the guidelines established by the China Council on Animal Care.

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Chen, H., Yu, S., Ma, R. et al. Hypoxia-activated XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of ΔNp63α expression and promote breast cancer metastasis independent of HIF1α. Cell Death Differ 31, 447–459 (2024). https://doi.org/10.1038/s41418-024-01271-z

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