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.

中文翻译：

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JMJD1/KDM3 表观遗传调节因子在癌症中的关键作用

表观遗传变化是癌症发展的根本原因之一，通常是由于修饰 DNA 或组蛋白的酶失调。大多数含有 Jumonji C 结构域 (JMJD) 的蛋白质是组蛋白赖氨酸去甲基化酶 (KDM)，因此是表观遗传调节剂。一个 JMJD 亚家族由 JMJD1A/KDM3A、JMJD1B/KDM3B 和 JMJD1C/KDM3C 组成，它们在氨基酸水平上大致相同 50%。所有三种 JMJD1 蛋白都能够从组蛋白 H3 上的赖氨酸 9 上去除二甲基和单甲基标记，并且还可能使精氨酸 3 和非组蛋白上的组蛋白 H4 去甲基化。对基因敲除小鼠的分析揭示了 JMJD1 蛋白在生育、肥胖、代谢综合征和心脏病中的关键作用。重要的是，大量研究表明，尤其是 JMJD1A 和 JMJD1C 在各种肿瘤中过度表达，刺激癌细胞增殖和侵袭，促进肿瘤有效生长。然而，JMJD1A 也可能抑制生殖细胞肿瘤的形成。同样，JMJD1B 似乎是急性髓细胞白血病的肿瘤抑制因子，但在其他癌症中是肿瘤促进因子。值得注意的是，通过降低组蛋白 H3 赖氨酸 9 的甲基化水平，JMJD1 蛋白可以显着改变转录组，从而影响肿瘤发生，包括通过上调 CCND1、JUN 和 MYC 等癌基因。JMJD1 蛋白的这种表观遗传活性对重金属、癌代谢物、氧和活性氧物质敏感，这些物质的水平在癌细胞内经常发生改变。总之，预计通过小分子抑制 JMJD1 酶活性对许多不同的癌症有益，