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Biological roles of LSD1 beyond its demethylase activity

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Abstract

It is well-established that Lysine-specific demethylase 1 (LSD1, also known as KDM1A) roles as a lysine demethylase canonically acting on H3K4me1/2 and H3K9me1/2 for regulating gene expression. Though the discovery of non-histone substrates methylated by LSD1 has largely expanded the functions of LSD1 as a typical demethylase, recent groundbreaking studies unveiled its non-catalytic functions as a second life for this demethylase. We and others found that LSD1 is implicated in the interaction with a line of proteins to exhibit additional non-canonical functions in a demethylase-independent manner. Here, we present an integrated overview of these recent literatures charging LSD1 with unforeseen functions to re-evaluate and summarize its non-catalytic biological roles beyond the current understanding of its demethylase activity. Given LSD1 is reported to be ubiquitously overexpressed in a variety of tumors, it has been generally considered as an innovative target for cancer therapy. We anticipate that these non-canonical functions of LSD1 will arouse the consideration that extending the LSD1-based drug discovery to targeting LSD1 protein interactions non-catalytically, not only its demethylase activity, may be a novel strategy for cancer prevention.

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Abbreviations

AR:

Androgen receptor

AML:

Acute myeloid leukemia

AOL:

Amine oxidase-like

CoREST:

REST (RE1-silencing transcription factor) corepressor

CPD:

Cdc4 phosphodegron

CREB:

CAMP-response element-binding protein

CtBP:

C-terminal-binding protein 1

Dnmt1:

DNA methyltransferase 1

E2F1:

Transcription factor

EMT:

Epithelial-to-mesenchymal transition

ER:

Estrogen receptor

ERRα:

Estrogen-related receptor α

GFI:

Growth factor independence

H3K4me1/2:

Mono- and di-methylated histone 3 lysine 4

H3K9me1/2:

Mono- and di-methylated histone 3 lysine 9

H4K20me2:

Di-methylated histone 4 lysine 20

HIF-1α:

Hypoxia-inducible factor-1

LSD1:

Lysine-specific demethylase 1

MAO:

Monoamine oxidase

MEF2:

Myocyte enhancer factor 2

NHEJ:

Nonhomologous end-joining

NuRD:

Nucleosome remodeling and deacetylase

PTMs:

Post-translational modifications

SCF:

SKP1-CUL1-F-box protein

STAT3:

Signal transducer and activator of transcription 3

SQSTM1:

Sequestasome 1

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Acknowledgements

This study was supported in part by the Natural Science Foundation of Zhejiang Province (20160171) (YZW), by the Ningbo Natural Science Foundation, China Grant (No. 2016A610148) (ZYY), and by the Medical Scientific Research Foundation of Zhejiang Province, China (Grant No. 2018KY689) (ZYY). Authors’ contributions: HYL had the idea for the article and providing the final approval of the version to be published. YXL was involved in performed the literature search and revision work, FYG was involved in drafting the manuscript. XXW and ZYY were involved in checking the language problems. YZW was involved in revising the manuscript critically for important scientific content. And the authors declare that they have no competing interests.

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  1. Feiying Gu and Yuxin Lin have contributed equally.

Authors and Affiliations

  1. Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China

    Feiying Gu, Zhun Wang, Yuezhen Wang & Huiyin Lan

  2. Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China

    Feiying Gu, Zhun Wang, Yuezhen Wang & Huiyin Lan

  3. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China

    Feiying Gu, Zhun Wang, Yuezhen Wang & Huiyin Lan

  4. Department of Oncology, Hospital of Chinese Medicine of Changxing County, Huzhou, 313100, China

    Yuxin Lin

  5. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Xiaoxin Wu

  6. Department of Respiratory Diseases, Hwa Mei Hospital, University of Chinese Academy Sciences, Ningbo, China

    Zhenyue Ye

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  1. Feiying Gu
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  3. Zhun Wang
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  4. Xiaoxin Wu
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Gu, F., Lin, Y., Wang, Z. et al. Biological roles of LSD1 beyond its demethylase activity. Cell. Mol. Life Sci. 77, 3341–3350 (2020). https://doi.org/10.1007/s00018-020-03489-9

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