Clinicopathologic significance of protein lysine methyltransferases in cancer
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REVIEW
Open Access
Clinicopathologic significance of protein lysine methyltransferases in cancer Theodore Vougiouklakis1†, Benjamin J. Bernard2†, Nupur Nigam2, Kyunghee Burkitt2, Yusuke Nakamura3 and Vassiliki Saloura2*
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. Keywords: Protein lysine methyltransferases, Clinicopathologic associations, Immunohistochemistry
Background It is well recognized that cancer is a genetic disease, though more recently it has become evident that epigenetic aberrations are also involved in critical steps of malignant transformation and progression. Protein lysine methyltransferases (PKMTs) constitute a large family of approximately 50 chromatin modifiers that mono-, diand/or tri-methylate lysine residues on histone and nonhistone substrates. These chromatin modifiers are responsible for the transcriptional regulation of specific downstream target genes, but may also affect the function of non-histone proteins by regulating post* Correspondence: [email protected] † Theodore Vougiouklakis and Benjamin J. Bernard are equally contributing first authors. 2 Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, 41 Medlars Drive, National Cancer Institute, Bethesda, MD 20892, USA Full list of author information is available at the end of the article
translational modifications, protein-protein interactions, protein stability, and subcompartmental cellular localization of non-histone substrates [1]. The Cancer Genome Atlas has revealed frequent genetic and expression alterations of PKMTs in multiple types of cancer [2, 3]. 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
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