Clinicopathologic significance of protein lysine methyltransferases in cancer

Abstract

Protein lysine methyltransferases (PKMTs) constitute a large family of approximately 50 chromatin modifiers that mono-, di- and/or tri-methylate lysine residues on histone and non-histone substrates. With the advent of The Cancer Genome Atlas, it became apparent that this family of chromatin modifiers harbors frequent genetic and expression alterations in multiple types of cancer. In this regard, past and ongoing preclinical studies have provided insight into the mechanisms of action of some of these enzymes, laying the ground for the ongoing development of PKMT inhibitors as novel anticancer therapeutics. The purpose of this review is to summarize existing data obtained by different research groups through immunohistochemical analysis of the protein expression levels of PKMTs, and their respective clinicopathologic associations. We focused on studies that used immunohistochemistry to associate protein expression levels of specific PKMTs, as well as several established histone methylation marks, with clinicopathologic features and survival outcomes in various cancer types. We also review ongoing clinical trials of PKMT inhibitors in cancer treatment. This review underscores the clinical relevance and potential of targeting the family of PKMT enzymes as the next generation of cancer therapy.

Lysine methyltransferase inhibitors: where we are now

“…As a result, these proteins have been related to several disease conditions such as cancer and neurodegeneration. [4][5][6][7][8] These findings make KMTs an appealing target for therapeutic intervention and encouraged the identification of modulators of these enzymes. A first group of KMTs includes around 55 members which share a common evolutionarily conserved SET [Su(var), 9 Enhancer of zeste, 10 Trithorax 11 ] domain which is responsible of the catalytic activity.…”

“…As a result, these proteins have been related to several disease conditions such as cancer and neurodegeneration. [4][5][6][7][8] These findings make KMTs an appealing target for therapeutic intervention Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, SA, Italy. E-mail: gsbardella@unisa.it; Fax: +39-089-96-9602; Tel: +39-089-96-9770…”

“…As a result, these proteins have been related to several disease conditions such as cancer and neurodegeneration. 4–8 These findings make KMTs an appealing target for therapeutic intervention and have encouraged the identification of modulators of these enzymes.…”

Downregulation of SETD5 Suppresses the Tumorigenicity of Hepatocellular Carcinoma Cells

“…Targeting epigenetic regulators has emerged as a promising approach to treat cancers associated with less distinctive genomic aberrations ( Cheng et al, 2019 ). KMTs containing well-conserved SET domains are among the druggable epigenetic regulators possibly exhibiting enzymatic activities ( Vougiouklakis et al, 2020 ). In this study, by analyzing the association of different KMT expression levels with liver cancer patient prognosis, we identified SETD5 as a novel putative KMT involved in liver cancer progression.…”

7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries are Potent and Selective Inhibitors of DNA Methyltransferase 1

“…[3] Similarly, it is attractive identifying probes or tools compounds to understand better epigenetic processes. Among the epigenetic drug and probe candidates, small molecules targeting epigenetic writers such as DNA methyltransferases (DNMTs) and protein lysine methyltransferases (PKMTs) are promising for the treatment of various types of cancer such as colorectal, breast, lung, ovarian, pancreatic cancer and acute myeloid leukemia, [4][5][6][7][8] neurological disorders, [9][10] autoimmune diseases, [11][12] and metabolic diseases. [13][14][15] DNA methylation is mediated by the enzyme family DNMTs that is responsible for catalyzing the covalent addition of a methyl group from S-adenosyl-L-methionine (SAM) to the 5-carbon of cytosine, mainly within CpG dinucleotides, yielding S-adenosyl-L-homocysteine (SAH).…”