The critical role of histone lysine demethylase KDM2B in cancer

Abstract

The discovery of histone demethylases has revealed the dynamic nature of the regulation of histone methylation. KDM2B is an important histone lysine demethylase that removes methyl from H3K36me2 and H3K4me3. It participates in many aspects of normal cellular processes such as cell senescence, cell differentiation and stem cell self-renewal. Recent studies also showed that KDM2B was overexpressed in various types of cancers. This review focuses primarily on the current knowledge of KDM2B and its function in cancer development.

Keywords: KDM2B; cancer; epigenetic regulation; histone demethylase.

Figure 1

Basic protein structure and biochemical characteristics of KDM2B. KDM2B consists of four distinct domains: a JmjC domain, a CxxC domain, a PHD domain, and an F-box domain. The JmjC domain exerts a function in binding H3K36me2; The CxxC domain is a DNA binding domain and specifically recognizes CpG islands; The PHD domain has E3 ubiquitin ligase activity and acts as a histone modification reader domain; The F-box domain acts as a linker protein between a target protein and an E3 ubiquitin ligase.

Figure 2

Mechanisms of KDM2B in regulating cell migration and senescence. KDM2B can bind directly to migration-associated genes to promote cell migration. Moreover, KDM2B promotes cell proliferation and inhibited cell senescence by repressing senescence-associated Ink4a/Arf/Ink4b locus and this function was via upregulation EZH2/H3K27me3 and H3K36me2/H3K4me3 demethylation.

Figure 3

Different mechanisms of KDM2B-induced cell differentiation suppression. KDM2B could recruit PRC1 to CpG islands of developmental genes via its CxxC-ZF domain. In addition, KDM2B also attracts a noncanonical PRC1 to the key cell differentiation-associated genes through the F-box domain. Becides, KDM2B can also directly inhibit the expression of differentiation markers.

Figure 4

Regulation of cell signaling pathways involved in cancers by KDM2B. First, the activation of FGF-2-KDM2B-EZH2 pathway contributes to cell proliferation, migration, angiogenesis and self-renewal of cancer stem cells. Second, KDM2B inhibits cell apoptosis by repressing c-Fos/c-FLIP pathway. Finally, KDM2B also activates PI3K/Akt/mTOR pathway and inhibits P53 pathway in cancers. In contrast, KDM2B also inhibits Wnt/β-catenin signaling pathway by inducing degradation of β-catenin.

Figure 5

Pivotal role of KDM2B in normal biological functions and cancer. As an important histone lysine demethylase, KDM2B is very important in regulating cell senescence, cell differentiation, stem cell self-renewal and somatic cell reprogramming. The dysregulation of KDM2B might contribute to cancer progression including cell proliferation, metastasis and drug resistance.

Figure 6

Overview of KDM2B mediated molecular mechanisms in cancer development. KDM2B acts as a double-edged sword in cancer development. On one hand, KDM2B inhibits p15^Ink4b pathway, increases oxidative phosphorylation and enhances KDM5A/MYC protein expression, which promotes cancer cell proliferation. Becides, KDM2B recruits PRC and Nsg2 to enhance cell migration and controls self-renewal of cancer stem cells. On the other hand, KDM2B inhibits ribosomal RNA genes, MYC protein, and promots c-Fos ubiquitylation, which led to a decrease of cancer cell proliferation.