Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer

Abstract

Epigenetic regulation of gene expression is crucial to the determination of cell fate in development and differentiation, and the Polycomb (PcG) and Trithorax (TrxG) groups of proteins, acting antagonistically as complexes, play a major role in this regulation. Although originally identified in Drosophila, these complexes are conserved in evolution and the components are well defined in mammals. Each complex contains a protein with methylase activity (KMT), which can add methyl groups to a specific lysine in histone tails, histone 3 lysine 27 (H3K27), by PcG complexes, and H3K4 and H3K36 by TrxG complexes, creating transcriptionally repressive or active marks, respectively. Histone demethylases (KDMs), identified later, added a new dimension to histone methylation, and mutations or changes in levels of expression are seen in both methylases and demethylases and in components of the PcG and TrX complexes across a range of cancers. In this review, we focus on both methylases and demethylases governing the methylation state of the suppressive and active marks and consider their action and interaction in normal tissues and in cancer. A picture is emerging which indicates that the changes which occur in cancer during methylation of histone lysines can lead to repression of genes, including tumour suppressor genes, or to the activation of oncogenes. Methylases or demethylases, which are themselves tumour suppressors, are highly mutated. Novel targets for cancer therapy have been identified and a methylase (KMT6A/EZH2), which produces the repressive H3K27me3 mark, and a demethylase (KDM1A/LSD1), which demethylates the active H3K4me2 mark, are now under clinical evaluation.

A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression

“…They showed that, although the protein is catalytically inactive, the mouse is viable and fertile, contrary to the KDM5B knockout mouse, which displays an embryonic lethal phenotype 43 . These data confirm several observations regarding the relevant biological effects of KDM5 demethylases that are not dependent on their catalytic activity 12,37,[44][45][46] . We hypothesized that the NTT protein could be recruited to genomic sites through the PHD domains and retain some noncatalytic regulatory functions of KDM5B and/or compete for the catalytic functions of the PLU-1 isoform.…”

“…The deregulated expression of KDM5 enzymes has been extensively documented in many cancer types and contributes significantly to tumor initiation and progression 12 . Specifically, KDM5B is a master regulator of H3K4-methylome in stem cells, development, and cancer 13 .…”

10th Anniversary of Cells: Advances in Cellular Immunology—Regulation of Autoimmune Response and Antitumor Reactivity: Are They Two Side of the Same Coin?

“…That epitranscriptomics and general epigenetic molecular mechanisms can play an essential role in determining the cell fate in development and differentiation is becoming increasingly clear [ 11 ]. Joyce Taylor-Papadimitriou and Joy M. Burchell have clearly shown the changes occurring in cancer determined by histone methylases and demethylases [ 12 ]. These epigenetic regulators can suppress the oncosuppressor genes and activate the oncogenes, leading to cancer progression [ 12 ].…”

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells

“…Histone acetylation and methylation are two major epigenetic marks that are removed by erasers, including the zinc-dependent histone deacetylases (HDACs) and the FAD-dependent lysine-specific demethylase 1 (LSD1, also known as KDM1A) that are both targets for EPIDD [ 5 , 6 ]. While LSD1 has a single well validated substrate in histone H3 [ 7 ], the eleven human HDAC isozymes are highly diverse in their function [ 8 ].…”