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LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis

Oncogene volume 36, pages 5512–5521 (2017)Cite this article

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Abstract

Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.

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Acknowledgements

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (No. 2015R1A2A1A10052578).

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Author notes

  1. J-Y Lee and J-H Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Republic of Korea

    J-Y Lee, J-H Park & G Kong

  2. Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea

    H-J Choi, H-Y Won, H-s Joo, D-H Shin & G Kong

  3. National Cancer Center, Goyang, Republic of Korea

    M K Park

  4. Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Korea

    B Han & K P Kim

  5. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, OH, USA

    T J Lee & C M Croce

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Lee, JY., Park, JH., Choi, HJ. et al. LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis. Oncogene 36, 5512–5521 (2017). https://doi.org/10.1038/onc.2017.158

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  • DOI: https://doi.org/10.1038/onc.2017.158

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