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LSD1 promotes S-phase entry and tumorigenesis via chromatin co-occupation with E2F1 and selective H3K9 demethylation

Oncogene volume 37, pages 534–543 (2018)Cite this article

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Abstract

Histone H3 lysine-9 (H3K9) methylation is essential for retinoblastoma protein (RB)-mediated heterochromatin formation, epigenetic silencing of S-phase genes and permanent cell cycle arrest or cellular senescence. Besides as an H3K4 demethylase, lysine-specific demethylase-1 (LSD1) has been shown to promote H3K9 demethylation. However, it is unexplored whether LSD1 has a causal role in regulating cell cycle entry and senescence. Here we demonstrate that genetic depletion or pharmacological inhibition of LSD1 triggers G1 arrest and cellular senescence. Genome-wide chromatin immunoprecipitation-sequencing analysis reveals that LSD1 binding sites overlap significantly with those bound by the S-phase gene transcription factor E2F1. Gene ontology analysis demonstrates that a large portion of E2F1 and LSD1 cotargeted genes are involved in cell cycle and proliferation. Further analyses show that depletion of LSD1 increases the level of H3K9me2 and thereby represses expression of the LSD1-E2F1 cotarget genes, but has no effects on H3K4me2 level in those loci. In contrast, knockdown of the H3K4me2 reader PHF8 decreases the H3K4me2 level at the LSD1-E2F1 cotargeted loci, but this effect is rescued by codepletion of LSD1. Furthermore, the enzymatic activity of LSD1 is essential for H3K9me2 demethylation at cell cycle gene loci. Notably, cotreatment of chemotherapeutic agent camptothecin enhanced LSD1 inhibitor-induced senescence and growth inhibition of cancer cells in vitro and in mice. Our data reveal LSD1 as a molecular rheostat selectively regulating H3K9 demethylation at cell cycle gene loci, thereby representing a key player in oncogenesis and a viable target for cancer therapy.

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Acknowledgements

We thank Binhua Zhou for plasmids. This work was supported in part by grants from the National Institutes of Health (CA134514, CA130908 and CA193239 to HH) and the Department of Defense (W81XWH-09-1-622 to HH).

Author contributions

HH conceived the study. YH, YZ, LW, LRB and YP performed the experiments. L(Liguo)W performed bioinformatics analysis of ChIP-seq data. YH, YZ and HH wrote the paper.

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  1. Y He, Y Zhao and L Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA

    Y He, Y Zhao, L Wang, Y Pan & H Huang

  2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    L R Bohrer

  3. Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA

    L Wang

  4. Department of Urology, Mayo Clinic College of Medicine, Rochester, MN, USA

    H Huang

  5. Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA

    H Huang

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He, Y., Zhao, Y., Wang, L. et al. LSD1 promotes S-phase entry and tumorigenesis via chromatin co-occupation with E2F1 and selective H3K9 demethylation. Oncogene 37, 534–543 (2018). https://doi.org/10.1038/onc.2017.353

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