Targeting protein lysine methylation and demethylation in cancers

Abstract

During the last decade, we saw an explosion of studies investigating the role of lysine methylation/demethylation of histones and non-histone proteins, such as p53, NF-kappaB, and E2F1. These 'Ying-Yang' post-translational modifications are important to fine-tuning the activity of these proteins. Lysine methylation and demethylation are catalyzed by protein lysine methyltransferases (PKMTs) and protein lysine demethylases (PKDMs). PKMTs, PKDMs, and their substrates have been shown to play important roles in cancers. Although the underlying mechanisms of tumorigenesis are still largely unknown, growing evidence is starting to link aberrant regulation of methylation to tumorigenesis. This review focuses on summarizing the recent progress in understanding of the function of protein lysine methylation, and in the discovery of small molecule inhibitors for PKMTs and PKDMs. We also discuss the potential and the caveats of targeting protein lysine methylation for the treatment of cancer.

LSD1-mediated epigenetic modification contributes to ovarian cancer cell migration and invasion

“…While the genetic changes in ovarian cancer have been extensively studied, the contribution of epigenetic alterations to ovarian cancer progression remains poorly understood. Histone methylation is a dynamic epigenetic process that has been found to be associated with cancer, including ovarian cancer (39). LSD1 is a well-characterized demethylase that can remove methyl groups from H3K4 (4).…”

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

“…In human cancers, it remains unclear whether H3K27 methylation is the only way by which Ezh2 controls tumorigenesis. Since Ezh2 has other substrates beyond histone H3, it was proposed that Ezh2 might facilitate tumorigenesis by regulating the activity of nonhistone substrates such as transcription factors (He et al 2012b;Kim et al 2013). Interestingly, skin papillomas of poorly differentiated K5-SOS-F mice show high levels of Ezh2 and express Fra-2 (data not shown).…”

Effect and mechanism of BET bromodomain inhibition in macrophage transcriptional programming

“…The implication of epigenetic regulation in gene expression has led to the targeting of transcriptional regulators that function on chromatin levels in the treatment of various diseases [8][9][10] . One promising drug target is the bromodomain and extra terminal domain (BET) family proteins (BrdT, Brd2, Brd3 and Brd4), which play important roles in histone acetylation-dependent transcriptional regulation [11] .…”