Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance

Abstract

Oxygen sensing is inherent among most animal lifeforms and is critical for organism survival. Oxygen sensing mechanisms collectively trigger cellular and physiological responses that enable adaption to a reduction in ideal oxygen levels. The major mechanism by which oxygen-responsive changes in the transcriptome occur are mediated through the hypoxia-inducible factor (HIF) pathway. Upon reduced oxygen conditions, HIF activates hypoxia-responsive gene expression programs. However, under normal oxygen conditions, the activity of HIF is regularly suppressed by cellular oxygen sensors; prolyl-4 and asparaginyl hydroxylases. Recently, these oxygen sensors have also been found to suppress the function of two lysine methyltransferases, G9a and G9a-like protein (GLP). In this manner, the methyltransferase activity of G9a and GLP are hypoxia-inducible and thus present a new avenue of low-oxygen signaling. Furthermore, G9a and GLP elicit lysine methylation on a wide variety of non-histone proteins, many of which are known to be regulated by hypoxia. In this article we aim to review the effects of oxygen on G9a and GLP function, non-histone methylation events inflicted by these methyltransferases, and the clinical relevance of these enzymes in cancer.

EHMT1/EHMT2 in EMT, cancer stemness and drug resistance: emerging evidence and mechanisms

“…EHMT1/2 levels are induced by hypoxia and exert tumorigenic effects via methylation of a wide range of histone and non‐histone substrates [44]. Consistently, recruitment of EHMT1/2 and concomitant H3K9me2/me3 at the E‐cadherin promoter were drastically increased during hypoxia.…”

Can Epigenetics Help Solve the Puzzle Between Concomitant Cardiovascular Injury and Severity of Coronavirus Disease 2019?

“…97 The regulation of HIF-1 after methylation promoted by G9a has an extensive implication on hypoxic gene expression programs, which is a consequence of HIF-1 capacity to control cellular hypoxic adaption. 98…”

“…97 The regulation of HIF-1 after methylation promoted by G9a has an extensive implication on hypoxic gene expression programs, which is a consequence of HIF-1 capacity to control cellular hypoxic adaption. 98 HIF-1 expression in the heart may have a protective function in short term because it regulates gene expression that allows the tissue to adapt to a low-oxygen environment. 99 However, long-term expression of stable HIF-1 in the myocardium may lead to cardiac damage and contribute to the evolution of HF.…”

The ferroxidase HEPHaestin in Lung cancer: Pathological Significance and Prognostic Value

“…The ferroxidase HEPH has recently emerged to play a role in breast tumour cell growth; in particular its decreased expression has been significantly correlated with a poor survival in affected patients (15). In order to expand the analysis to other cancer types we examined HEPH expression using UALCAN that analyse TCGA RNA-sequencing and patients' clinical data from 33 different cancer types, including several metastatic tumors (22).…”

“…We recently identified a single-nucleotide polymorphism within HEPH gene, leading to a missense variation of this multicopper ferroxidase, which results protective against asbestos-dependent malignant pleural mesothelioma and lung carcinoma (13, 14). Moreover, in breast cancer HEPH expression has been shown to be down-regulated by the histone methyltransferase G9a, leading to changes in iron homeostasis that burst cancer growth (15).…”