Histone proteins also plays a crucial role within the regulation of a variety of signaling pathways. For example, the functions of p53 and RB1, two essential tumor suppressor proteins, are sophisticatedly regulated by lysine methylation.(1) As the detailed molecular mechanisms of non-histone methylation have been described in an additional overview Anemoside B4 web article,(1) we here comment on quite a few important points relevant to methylation of non-histone proteins. There are actually at least 5 principal functions of methylation on non-histone proteins as follows: (i) it affects other kinds of modifications like phosphorylation on substrates; (ii) it influences protein rotein interactions; (iii) it regulates stability of substrate proteins; (iv) it defines subcellular localization of substrates; and (v) it impacts the promoter binding affinity of substrate proteins (Fig. 1). On the basis of those characteristics, methylation of non-histone proteins is involved in several biological processes inside the cell.Dysregulation of protein lysine methyltransferases in human cancerIt has been reported that a variety of protein lysine methyltransferases are involved in human cancers as shown in Table 1. We selected several pivotal enzymes as targets for anticancer therapy developed, and detail their qualities under. SET and MYND domain-containing proteins. We previously reported that SMYD3 is overexpressed in colorectal cancer, hepatocellular carcinoma, and breast cancer, and possesses histone lysine methyltransferase activity.(2,20,21) Because then, multiple reports have shown that dysregulation of SMYD3 is involved in quite a few sorts of cancer.(1) Reduction of SMYD3 expression leads to suppression of cancer cell development and induction of apoptosis.(2,20) Therefore, SMYD3 is now viewed as as one of many critical targets for anticancer therapy. Along with histone proteins, vascular endothelial development element receptor 1 and MAP3K2 had been reported as substrates of SMYD3.(22,23) Two particular inhibitors targeting PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/21338877 enzyme activity of SMYD3 had been reported not too long ago; one is BCI-121, which could suppress the growth of different varieties of cancer cells overexpressing SMYD3.(24) The other is EPZ031686, which showed very good bioavailability following oral dosing in mice.(25) We also reported that SMYD2, a family members member of SMYD methyltransferases, is overexpressed in many kinds of cancer.(26) Given that knockdown of SMYD2 induces suppression of cancer cell development,(26,27) it is also deemed a important target for anticancer therapy. We and other people have reported various substrates of SMYD2 like histone H3, p53, RB1, heat shock protein 90AB1, poly (ADP-ribose) polymerase 1, and phosphatase and tensin homolog.(1,280) In unique, as SMYD2 was reported to inactivate functions of tumor suppressor proteins p53 and RB1 via lysine methylation, it seems to serve as an oncogenic protein. As a result, inhibitors targeting SMYD2 enzyme activity have been actively develCancer Sci April 2016 vol. 107 no. four oped. AZ-505, the first reported SMYD2 specific inhibitor, showed an IC50 worth of 120 nM (enzyme inhibition); in this improvement procedure, p53 peptide was employed as a substrate.(31) Later, Nguyen et al.(32) reported that LLY-507 worked as a precise inhibitor of SMYD2, which showed an IC50 of 15 nM (enzyme inhibition). LLY-507 also inhibited SMYD2mediated p53 methylation in U2OS cells with an IC50 of 0.6 lM, implying that LLY-507 can be a selective and cell-active tiny molecule inhibitor of SMYD2. Sweis et al.(33).