The Emerging Role of H3K9me3 as a Potential Therapeutic Target in Acute Myeloid Leukemia

Abstract

Growing evidence has demonstrated that epigenetic dysregulation is a common pathological feature in human cancer cells. Global alterations in the epigenetic landscape are prevalent in malignant cells across different solid tumors including, prostate cancer, non-small-cell lung cancer, renal cell carcinoma, and in haemopoietic malignancy. In particular, DNA hypomethylation and histone hypoacetylation have been observed in acute myeloid leukemia (AML) patient blasts, with histone methylation being an emerging area of study. Histone 3 lysine 9 trimethylation (H3K9me3) is a post-translational modification known to be involved in the regulation of a broad range of biological processes, including the formation of transcriptionally silent heterochromatin. Following the observation of its aberrant methylation status in hematological malignancy and several other cancer phenotypes, recent studies have associated H3K9me3 levels with patient outcome and highlighted key molecular mechanisms linking H3K9me3 profile with AML etiology in a number of large-scale meta-analysis. Consequently, the development and application of small molecule inhibitors which target the histone methyltransferases or demethylase enzymes known to participate in the oncogenic regulation of H3K9me3 in AML represents an advancing area of ongoing study. Here, we provide a comprehensive review on how this particular epigenetic mark is regulated within cells and its emerging role as a potential therapeutic target in AML, along with an update on the current research into advancing the generation of more potent and selective inhibitors against known H3K9 methyltransferases and demethylases.

Transcription Analysis of a Histones Modifiers Panel Coupled with Tumor Suppressor Genes Displayed Frequent Changes in Acute Myeloid Leukemia-Related Genes

“…In corroboration with the previous studies [46], our results demonstrated that SUV39H1, which acts as an important H3K9 methyltransferase, adversely correlated with the expression of p16 INK4A and p53 gens.…”

“…Overexpression of PRDM16 has been demonstrated in approximately 30% of AML patients, which was associated with poor prognosis [44]. A great deal of evidence is already in hand that explores the suppressive role of SUV39H1 on TSGs in the AML patients [45]. The synoptic conclusion from these studies could be that SUV39H1 is required for the formation of AML largely through transcriptional repression of p15, p21 and E-cadherin [45].…”

“…A great deal of evidence is already in hand that explores the suppressive role of SUV39H1 on TSGs in the AML patients [45]. The synoptic conclusion from these studies could be that SUV39H1 is required for the formation of AML largely through transcriptional repression of p15, p21 and E-cadherin [45]. Moreover, the results of their study also declared that SUV39H1 inhibition could induce differentiation and apoptosis in AML cells by restoring the expression of epigenetically silenced genes [45].…”

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

“…Additionally, more and more evidences demonstrated that histone modifications in glioblastoma, mainly including histone acetylation and methylation, may determine the development of this cancer (Romani et al, 2018). H3K9 methylation and its methyltransferase G9a are also considered as a prominent mechanism in cancer cell biology and a potential therapeutic target in cancer treatment (Casciello et al, 2015;Janardhan et al, 2018;Cao et al, 2019;Monaghan et al, 2019). Although the inhibitor of G9a was reported to sensitize glioma cells to TMZ and to induce the differentiation of glioma stem-like cell, the detailed correlations between G9a and glioblastoma genesis remains to be further elucidated.…”

SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia

“…Although the interest in developing leukemia therapies by targeting H3K9 methyltransferases is increasing [ 41 ], the role of Suv39h1 and its associated H3K9me3 modification in MLL -r AML remains unclear. In the present study, we provide insight into the significance of Suv39h1 in regulating MLL -r leukemia and LSCs.…”