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H3K4 demethylase KDM5B regulates cancer cell identity and epigenetic plasticity

Oncogene volume 41, pages 2958–2972 (2022)Cite this article

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Abstract

The H3K4 demethylase KDM5B is overexpressed in multiple cancer types, and elevated expression levels of KDM5B is associated with decreased survival. However, the underlying mechanistic contribution of dysregulated expression of KDM5B and H3K4 demethylation in cancer is poorly understood. Our results show that loss of KDM5B in multiple types of cancer cells leads to increased proliferation and elevated expression of cancer stem cell markers. In addition, we observed enhanced tumor formation following KDM5B depletion in a subset of representative cancer cell lines. Our findings also support a role for KDM5B in regulating epigenetic plasticity, where loss of KDM5B in cancer cells with elevated KDM5B expression leads to alterations in activity of chromatin states, which facilitate activation or repression of alternative transcriptional programs. In addition, we define KDM5B-centric epigenetic and transcriptional patterns that support cancer cell plasticity, where KDM5B depleted cancer cells exhibit altered epigenetic and transcriptional profiles resembling a more primitive cellular state. This study also provides a resource for evaluating associations between alterations in epigenetic patterning upon depletion of KDM5B and gene expression in a diverse set of cancer cells.

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Fig. 1: KDM5B expression in cancer and establishment of cancer cell models.
Fig. 2: KDM5B regulates the transcriptional repertoire of cancer cells.
Fig. 3: Integrative transcriptome analysis reveals that loss of KDM5B leads to increased expression of stemness genes and an expression signature consistent with multiple cancers.
Fig. 4: Loss of KDM5B leads to epigenetic reprogramming of H3K4me3 in cancer cells.
Fig. 5: Breadth of H3K4me3 domains is linked to cancer cell identity.
Fig. 6: Functional and morphological characteristics of KDM5B depleted cancer cells.
Fig. 7: Altered expression of cancer stem cell markers following loss of KDM5B.

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Data availability

The sequencing data from this study have been submitted to the NCBI Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE165959.

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Acknowledgements

This work utilized the Wayne State University High Performance Computing Grid for computational resources (https://www.grid.wayne.edu/). Flow cytometry was performed in the Microscopy, Imaging, and Cytometry Resources (MICR) core at the Karmanos Cancer Institute and Wayne State University. We thank Lisa Polin for helpful discussions.

Funding

This work was supported by Wayne State University, Karmanos Cancer Institute, and a grant from the Elsa U. Pardee Foundation awarded to BLK.

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Author notes

  1. Besa Xhabija

    Present address: Department of Chemistry and Biochemistry, University of Michigan-Flint, Flint, MI, USA

  2. Jiji T. Kurup

    Present address: The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

Authors and Affiliations

  1. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

    Runsheng He, Besa Xhabija, Lijin K. Gopi, Jiji T. Kurup, Zhishan Xu & Benjamin L. Kidder

  2. Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    Runsheng He, Besa Xhabija, Lijin K. Gopi, Jiji T. Kurup, Zhishan Xu & Benjamin L. Kidder

  3. Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, 453000, Henan, PR China

    Zhishan Xu

  4. College of Chemistry, Chemistry Engineering and Materials Science, Shandong Normal University, Jinan, 250014, Shandong, PR China

    Zhishan Xu

  5. Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, Shandong, PR China

    Zhe Liu

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BLK conceived of the study, designed, and performed experiments, analyzed the data, and drafted the manuscript. RH, BX, and ZX performed experiments. LKG and JTK assisted with computational analyses.

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He, R., Xhabija, B., Gopi, L.K. et al. H3K4 demethylase KDM5B regulates cancer cell identity and epigenetic plasticity. Oncogene 41, 2958–2972 (2022). https://doi.org/10.1038/s41388-022-02311-z

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