Crucial Functions of the JMJD1/KDM3 Epigenetic Regulators in Cancer

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.