Epigenetic Warriors Against Cancer: Targeting Histone Methyltransferases and Lysine Demethylases

Verma SK, Knight SD. Recent progress in the discovery of small-molecule inhibitors of the HMT EZH2 for the treatment of cancer. 
Future Med Chem. 2013;5(14):1661-1670. doi:10.4155/fmc.13.136

Histone modifications are pivotal regulators of gene expression, and their dysregulation is implicated in the development and progression of cancer. Among these modifications, histone methylation, controlled by histone methyltransferases(HMTs) and histone lysine demethylases(KDMs), holds immense potential as a therapeutic target in the battle against this debilitating and deadly disease. This article explores the dynamics of HMTs and KDMs in cancer and the promising strategies to home in on these enzymes for remedial purposes.

Histone Methyltransferases

HMTs, also known as "writers," are enzymes responsible for the addition of methyl groups to specific lysine or arginine residues on histone tails. Depending on the particular lysine or arginine residue being modified and the number of methyl groups added, histone methylation can result in either gene activation or repression. For example, methylated histone marks like H3K4me1/2/3, H3K36me3, and H3K79me2 have been identified as transcription activators, whereas tri-methylated H3K9 and H3K27 are known to play repressive roles.

One of the most studied HMT families is the enhancer of zeste homolog 2 (EZH2), which catalyzes the mono-, di-, and tri-methylation of lysine 27 on histone H3 (H3K27me1/2/3). In many cancer types, EZH2 is overexpressed, causing global changes in histone methylation patterns and promoting tumorigenesis. Overexpression of other HMTs, such as the histone H3K79 methyltransferase DOT1L (disruptor of telomeric silencing 1-like) and EZH1, has also been linked to various cancers.

Histone Lysine Demethylases

KDMs, also referred to as "erasers," remove methyl groups from histone lysine residues, thereby altering the chromatin state and gene expression. KDMs are categorized into two main families: the amine oxidase KDM1 and the Jumonji C (JmjC) domain-containing KDMs. KDM1 primarily demethylates H3K4me1/2 and H3K9me1/2, while the JmjC domain-containing KDMs have diverse specificities, such as KDM3A (H3K9me1/2), KDM4A/B/C (H3K9me2/3 and H3K36me2/3), KDM5A-D (H3K4me2/3), and KDM6A/B (H3K27me2/3). Dysregulation of KDMs has been observed in various cancers and is associated with abnormal gene expression profiles that drive tumorigenesis.

Targeting HMTs and KDMs in Cancer

Given their pivotal roles in cancer development, HMTs and KDMs have emerged as attractive marks for cancer therapy. Several approaches are being explored to inhibit or modulate the activity of these enzymes. 

Pharmaceutical companies are actively generating small molecule inhibitorsdirected at specific HMTs and KDMs. For instance, GSK126 and EPZ-6438 are selective inhibitors of EZH2, which have shown encouraging results in preclinical studies and early-phase clinical trials for certain cancers, including lymphomas. EZH2 is frequently overexpressed or mutated in certain cancer types, leading to global alterations in histone methylation patterns that can cause the aberrant repression of tumor suppressor genes and other genes involved in controlling cell growth and differentiation. By inhibiting EZH2, these compounds can reverse the silencing of tumor suppressor genes that are transcriptionally inactivated by methylated H3K27. 

Subsequent reactivation of tumor suppressors can effectuate the restoration of normal cellular functions, such as apoptosis and cell cycle regulation, which are often impaired in cancer cells. This can lead to a decrease in cell proliferation and a reduced ability of cancer cells to divide uncontrollably. These compounds have also been shown to promote the differentiation of cancer cells. 

Differentiated cells are often less proliferative and more sensitive to other therapeutic interventions, making them less aggressive and easier to target.

In addition to single-target inhibitors, researchers are investigating multi-target inhibitorsthat can simultaneously hinder multiple HMTs or KDMs. This tactic aims to counteract the redundancy among these enzymes, potentially achieving greater therapeutic effects. Combinationsof HMT or KDM inhibitors with other cancer therapies, such as chemotherapy or immunotherapy, are being explored. This strategy aims to exploit synergistic effects and overcome drug resistance, offering new avenues for improved cancer treatment. Epigenetic modulators, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, can indirectly influence HMT and KDM activities by transforming the chromatin landscape. Combinatorial epigenetic therapies are showing promise in preclinical studies and clinical trials for various cancer types.

Challenges and Future Perspectives

HMTs and KDMs are critical players in cancer development, offering prospective targets for epigenetic cancer regimens. Inhibiting or modulating the activity of these enzymes represents a cutting-edge method to reshape the cancer epigenome and restore normal gene expression patterns, ultimately leading to more effective and personalized cancer care.

Despite significant headway in pursuing HMTs and KDMs for cancer treatment, challenges remain, including achieving specificity, avoiding off-target effects, and understanding the complexities of histone modifications in different cancer contexts. Additionally, resistance mechanisms to targeted therapies may emerge, necessitating continuous research and generation of innovative strategies. Rapid and high-throughput means of measuring the activity and screening the inhibition of HMTs and KDMs would undoubtedly facilitate the evolution of novel epigenetic drugs against these histone modifiers. EpigenTek's ELISA-based EpiQuik™ and Epigenase™ Histone Methyltransferase Assaysand Histone Demethylase Assaysoffer a quick and convenient means of HMT or KDM activity/inhibition assessment in a simple, microplate-based format.