Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Abstract

Proteins are regulated by an incredible array of posttranslational modifications (PTMs). Methylation of lysine residues on histone proteins is a PTM with well-established roles in regulating chromatin and epigenetic processes. The recent discovery that hundreds and likely thousands of nonhistone proteins are also methylated at lysine has opened a tremendous new area of research. Major cellular pathways involved in cancer, such as growth signaling and the DNA damage response, are regulated by lysine methylation. Although the field has developed quickly in recent years many fundamental questions remain to be addressed. We review the history and molecular functions of lysine methylation. We then discuss the enzymes that catalyze methylation of lysine residues, the enzymes that remove lysine methylation, and the cancer pathways known to be regulated by lysine methylation. The rest of the article focuses on two open questions that we suggest as a roadmap for future research. First is understanding the large number of candidate methyltransferase and demethylation enzymes whose enzymatic activity is not yet defined and which are potentially associated with cancer through genetic studies. Second is investigating the biological processes and cancer mechanisms potentially regulated by the multitude of lysine methylation sites that have been recently discovered.

Figure 1.

Lysine residues can be modified by the addition of up to three methyl groups at the ε-nitrogen. Lysine methylation is catalyzed by lysine methyltransferase enzymes (KMTs) and removed by lysine demethylase enzymes (KDMs). Methylation states of lysine are recognized by protein “reader domains” that bind to specific methyl or nonmethyl states of their target proteins.

Figure 2.

SET domain proteins categorized by their established substrate specificity for (1) histone proteins, (2) nonhistone proteins, or (3) orphan enzymes with no well-established enzymatic activity. Note that there are enzymes that are primarily histone lysine methyltransferase enzymes (KMTs) but also have reported nonhistone substrates. In addition, there are proteins that are primarily nonhistone KMTs, with reports of histone methylation activity. We note that several PRDMs (e.g., 1, 2, 3, and 16) have been reported to have activity on H3K9 and more work is needed to understand the catalytic activities of these enyzmes.

Figure 3.

Proteins modified by lysine methylation from the PhosphoSitePlus database were mapped onto the Kyoto Encyclopedia of Genes and Genomes (KEGG) prostate cancer pathway. The figure shows a simplified pathway diagram; methylated proteins are indicated by a star.