Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease

Abstract

Protein lysine methylation is a crucial post-translational modification that regulates the functions of both histone and non-histone proteins. Deregulation of the enzymes or'writers' of protein lysine methylation, lysine methyltransferases (KMTs), is implicated in the cause of many diseases, including cancer, mental health disorders and developmental disorders. Over the past decade, significant advances have been made in developing drugs to target KMTs that are involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was recently approved for the treatment of epithelioid sarcoma and follicular lymphoma, and several more are in clinical and preclinical evaluation. Beyond chromatin, the many KMTs that regulate protein synthesis and other fundamental biological processes are emerging as promising new targets for drug development to treat diverse diseases.Covalent post-translational modifications (PTMs) of proteins are a major source of molecular functional diversity in mammalian cells, and their aberrant regulation is a ✉

Epigenetic Regulatory Dynamics in Models of Methamphetamine-Use Disorder

“…Writers include histone acetyl transferase (HATs), histone methyl transferase (KMTs/HMTs), and SET family of methyl transferase (SUV). These enzymes target promoters and enhancers to facilitate transcriptional activation [22][23][24]. Erasers include histone deacetylases (HDACs) and demethylases (KDM), which govern transcriptional repression [25,26].…”

NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer

“…Although recent molecular analysis of human HNSCC cancer cell lines with and without NSD1 mutations (generated by CRISPR/Cas9 genome editing) revealed aberrant regulation of genes related to oxidative phosphorylation, MYC, mTORC1 or RAS signaling and other pathways, the impact on the cell biology has not been addressed and no particular transformation effector genes have been validated [ 65 ]. In addition, further studies are necessary to show whether the disease phenotypes with aberrant functional NSD1 dose are purely the consequence of its chromatin regulatory role or whether yet to be identified non-chromatin NSD1 substrate proteins are critically involved [ 3 ].…”

“…Genetic lesions (mutations, translocations) as well as altered gene expression functionally affecting KMTs are recurrently found in various human malignancies but also in developmental disorders [ 2 ]. An increasing number of compounds that selectively target aberrantly activated KMTs have been developed and underwent clinical trials as novel cancer therapeutics [ 3 ]. In this review, we summarize the current knowledge on the nuclear receptor binding SET domain protein 1 (NSD1, aka KMT3B), a H3 lysine 36 (H3K36) methyltransferase that has recently gained attention because of its critical role in several human pathologies, such as germline developmental syndromes and cancers.…”

Genetic screen for suppressors of increased silencing in rpd3 mutants in Saccharomyces cerevisiae identifies a potential role for H3K4 methylation

“…These studies are significant to gain a deeper understanding of the interplay and crosstalk of chromatin writers, erasers, and readers ( Allis and Jenuwein 2016 ) but may also have relevance to current proposed applications of HDAC and other chromatin modification enzyme inhibitors in health care ( West and Johnstone 2014 ; Ansari 2019 ; Bhat et al 2021 ; Dang and Wei 2021 ). While therapeutic results have been seen using drugs that inhibit chromatin enzymes, the global effects of removing one chromatin-modifying activity on the myriad of others and all possible interactions and potential side-effects are not fully characterized.…”