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Crucial Functions of the JMJD1/KDM3 Epigenetic Regulators in Cancer

Yuan Sui, Ruicai Gu and Ralf Janknecht
Yuan Sui
1Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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Ruicai Gu
2Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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Ralf Janknecht
1Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
2Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
3Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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  • For correspondence: ralf-janknecht@ouhsc.edu
DOI: 10.1158/1541-7786.MCR-20-0404 Published January 2021
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Abstract

Epigenetic changes are one underlying cause for cancer development and often due to dysregulation of enzymes modifying DNA or histones. Most Jumonji C domain-containing (JMJD) proteins are histone lysine demethylases (KDM) and therefore epigenetic regulators. One JMJD subfamily consists of JMJD1A/KDM3A, JMJD1B/KDM3B, and JMJD1C/KDM3C that are roughly 50% identical at the amino acid level. All three JMJD1 proteins are capable of removing dimethyl and monomethyl marks from lysine 9 on histone H3 and might also demethylate histone H4 on arginine 3 and nonhistone proteins. Analysis of knockout mice revealed critical roles for JMJD1 proteins in fertility, obesity, metabolic syndrome, and heart disease. Importantly, a plethora of studies demonstrated that especially JMJD1A and JMJD1C are overexpressed in various tumors, stimulate cancer cell proliferation and invasion, and facilitate efficient tumor growth. However, JMJD1A may also inhibit the formation of germ cell tumors. Likewise, JMJD1B appears to be a tumor suppressor in acute myeloid leukemia, but a tumor promoter in other cancers. Notably, by reducing methylation levels on histone H3 lysine 9, JMJD1 proteins can profoundly alter the transcriptome and thereby affect tumorigenesis, including through upregulating oncogenes such as CCND1, JUN, and MYC. This epigenetic activity of JMJD1 proteins is sensitive to heavy metals, oncometabolites, oxygen, and reactive oxygen species, whose levels are frequently altered within cancer cells. In conclusion, inhibition of JMJD1 enzymatic activity through small molecules is predicted to be beneficial in many different cancers, but not in the few malignancies where JMJD1 proteins apparently exert tumor-suppressive functions.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:3–13

  • Received May 3, 2020.
  • Revision received June 17, 2020.
  • Accepted June 24, 2020.
  • Published first June 30, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (1)
January 2021
Volume 19, Issue 1
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Crucial Functions of the JMJD1/KDM3 Epigenetic Regulators in Cancer
Yuan Sui, Ruicai Gu and Ralf Janknecht
Mol Cancer Res January 1 2021 (19) (1) 3-13; DOI: 10.1158/1541-7786.MCR-20-0404

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Crucial Functions of the JMJD1/KDM3 Epigenetic Regulators in Cancer
Yuan Sui, Ruicai Gu and Ralf Janknecht
Mol Cancer Res January 1 2021 (19) (1) 3-13; DOI: 10.1158/1541-7786.MCR-20-0404
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  • Article
    • Abstract
    • Introduction
    • The Normal: Upkeeping a Variety of Biological Functions
    • The Good: Keeping Tumors in Check
    • The Bad: Contribution to Tumorigenesis
    • Hypoxia and JMJD1 Activity
    • JMJD1 Modulation by (Onco)metabolites
    • Inactivation through Losing the Grip on Iron
    • Beyond Epigenetics
    • Conclusion
    • Authors' Disclosures
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Molecular Cancer Research
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