Insight into the multi-faceted role of the SUV family of H3K9 methyltransferases in carcinogenesis and cancer progression.
Saha Nirmalya,Muntean Andrew G
Biochimica et biophysica acta. Reviews on cancer
Growing evidence implicates histone H3 lysine 9 methylation in tumorigenesis. The SUV family of H3K9 methyltransferases, which include G9a, GLP, SETDB1, SETDB2, SUV39H1 and SUV39H2 deposit H3K9me1/2/3 marks at euchromatic and heterochromatic regions, catalyzed by their conserved SET domain. In cancer, this family of enzymes can be deregulated by genomic alterations and transcriptional mis-expression leading to alteration of transcriptional programs. In solid and hematological malignancies, studies have uncovered pro-oncogenic roles for several H3K9 methyltransferases and accordingly, small molecule inhibitors are being tested as potential therapies. However, emerging evidence demonstrate onco-suppressive roles for these enzymes in cancer development as well. Here, we review the role H3K9 methyltransferases play in tumorigenesis focusing on gene targets and biological pathways affected due to misregulation of these enzymes. We also discuss molecular mechanisms regulating H3K9 methyltransferases and their influence on cancer. Finally, we describe the impact of H3K9 methylation on therapy induced resistance in carcinoma. Converging evidence point to multi-faceted roles for H3K9 methyltransferases in development and cancer that encourages a deeper understanding of these enzymes to inform novel therapy.
Insights for the design of protein lysine methyltransferase G9a inhibitors.
Charles Mariasoosai Ramya Chandar,Dhayalan Arunkumar,Hsieh Hsing-Pang,Coumar Mohane Selvaraj
Future medicinal chemistry
The epigenetic control of gene expression could be affected by addition and/or removal of post-translational modifications such as phosphorylation, acetylation and methylation of histone proteins, as well as methylation of DNA (5-methylation on cytosines). Misregulation of these modifications is associated with altered gene expression, resulting in various disease conditions. G9a belongs to the protein lysine methyltransferases that specifically methylates the K9 residue of histone H3, leading to suppression of several tumor suppressor genes. In this review, G9a functions, role in various diseases, structural biology aspects for inhibitor design, structure-activity relationship among the reported inhibitors are discussed which could aid in the design and development of potent G9a inhibitors for cancer treatment in the future.
Epigenetics and memory: Emerging role of histone lysine methyltransferase G9a/GLP complex as bidirectional regulator of synaptic plasticity.
Pang Karen Ka Lam,Sharma Mahima,Sajikumar Sreedharan
Neurobiology of learning and memory
Various epigenetic modifications, including histone lysine methylation, play an integral role in learning and memory. The importance of the histone lysine methyltransferase complex G9a/GLP and its associated histone H3 lysine K9 dimethylation in memory formation and cognition, has garnered the attention of researchers in the past decade. Recent studies feature G9a/GLP as the 'bidirectional regulator of synaptic plasticity', the neural correlate of memory. As the 'title' suggests, G9a/GLP participates in the maintenance of both long-term potentiation (LTP) and long-term depression (LTD). This complex is demonstrated to mostly suppress LTP-related plasticity-related products (PRPs). Notably, our recent paper also shows that G9a/GLP facilitates LTD maintenance in intact hippocampal slices - shedding light on the overlooked influence of epigenetics on LTD. Although the exact mechanisms of G9a/GLP activity regulation in cognition remain elusive, pharmacological inhibition of G9a/GLP presents a new avenue of therapeutic intervention in epigenetic dysfunction-related cognitive deficits.
Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents.
Cao Hao,Li Ling,Yang Deying,Zeng Liming,Yewei Xie,Yu Bin,Liao Guochao,Chen Jianjun
European journal of medicinal chemistry
Epigenetics is the study of heritable changes in gene expression without changing the DNA sequence - a change in phenotype without a change in genotype. Epigenetic abnormalities can lead to serious diseases such as cancer in organisms. Histone methylation is one of the several manifestations of epigenetics, and requires specific enzymes to catalyze, for example, G9a, which is a histone methyl transferase. G9a catalyzes the methylation of histone 3 lysine 9 (H3K9) and histone 3 lysine 27 (H3K27). In addition, G9a also plays an essential role in DNA replication, damage and repair, and gene expression by regulating DNA methylation. Moreover, G9a has been found to be overexpressed in many tumor cells and is associated with the occurrence and development of tumors. Because of its unique characteristics, G9a has become a very promising target for anti-cancer agents. Over the last decade, dozens of G9a inhibitors have been discovered as potential anticancer therapeutic agents. In this review, we summarize and classify current G9a inhibitors, the challenges and future direction are also discussed in detail.
Targeting H3K9 methyltransferase G9a and its related molecule GLP as a potential therapeutic strategy for cancer.
Rahman Ziaur,Bazaz Mohd Rabi,Devabattula Geetanjali,Khan Mohd Abrar,Godugu Chandraiah
Journal of biochemical and molecular toxicology
H3K9 methyltransferase (G9a) and its relevant molecule GLP are the SET domain proteins that specifically add mono, di and trimethyl groups on to the histone H3K9, which lead to the transcriptional inactivation of chromatin and reduce the expression of cancer suppressor genes, which trigger growth and progress of several cancer types. Various studies have demonstrated that overexpression of H3K9 methyltransferase G9a and GLP in different kinds of tumors, like lung, breast, bladder, colon, cervical, gastric, skin cancers, hepatocellular carcinoma and hematological malignancies. Several G9a and GLP inhibitors such as BIX-01294, UNC0642, A-366 and DCG066 were developed to combat various cancers; however, there is a need for more effective and less toxic compounds. The current molecular docking study suggested that the selected new compounds such as ninhydrin, naphthoquinone, cysteamine and disulfide cysteamine could be suitable molecules as a G9a and GLP inhibitors. Furthermore, detailed cell based and preclinical animal studies are required to confirm their properties. In the current review, we discussed the role of G9a and GLP mediated epigenetic regulation in the cancers. A thorough literature review was done related to G9a and GLP. The databases used extensively for retrieval of information were PubMed, Medline, Scopus and Science-direct. Further, molecular docking was performed using Maestro Schrodinger version 9.2 software to investigate the binding profile of compounds with Human G9a HMT (PDB ID: 3FPD, 3RJW) and Human GLP MT (PDB ID: 6MBO, 6MBP).
Targeting EHMT2/ G9a for cancer therapy: Progress and perspective.
Jan Suraya,Dar Mohd Ishaq,Wani Rubiada,Sandey Jagjeet,Mushtaq Iqra,Lateef Sammar,Syed Sajad Hussain
European journal of pharmacology
Euchromatic histone lysine methyltransferase-2, also known as G9a, is a ubiquitously expressed SET domain-containing histone lysine methyltransferase linked with both facultative and constitutive heterochromatin formation and transcriptional repression. It is an essential developmental gene and reported to play role in embryonic development, establishment of proviral silencing in ES cells, tumor cell growth, metastasis, T-cell immune response, cocaine induced neural plasticity and cognition and adaptive behavior. It is mainly responsible for carrying out mono, di and tri methylation of histone H3K9 in euchromatin. G9a levels are elevated in many cancers and its selective inhibition is known to reduce the cell growth and induce autophagy, apoptosis and senescence. We carried out a thorough search of online literature databases including Pubmed, Scopus, Journal websites, Clinical trials etc to gather the maximum possible information related to the G9a. The main messages from the cited papers are presented in a systematic manner. Chemical structures were drawn by Chemdraw software. In this review, we shed light on current understanding of structure and biological activity of G9a, the molecular events directing its targeting to genomic regions and its post-translational modification. Finally, we discuss the current strategies to target G9a in different cancers and evaluate the available compounds and agents used to inhibit G9a functions. The review provides the present status and future directions of research in targeting G9a and provides the basis to persuade the development of novel strategies to target G9a -related effects in cancer cells.