Regulation of chromatin structure via histone post-translational modification and the link to carcinogenesis

Abstract

The loss of genome integrity contributes to the development of tumors. Although genome instability is associated with virtually all tumor types including both solid and liquid tumors, the aberrant molecular origins that drive this instability are poorly understood. It is now becoming clear that epigenetics and specific histone post-translational modifications (PTMs) have essential roles in maintaining genome stability under normal conditions. A strong relationship exists between aberrant histone PTMs, genome instability, and tumorigenesis. Changes in the genomic location of specific histone PTMs or alterations in the steady-state levels of the PTM are the consequence of imbalances in the enzymes and their activities catalyzing the addition of PTMs ("writers") or removal of PTMs ("erasers"). This review focuses on the misregulation of three specific types of histone PTMs: histone H3 phosphorylation at serines 10 and 28, H4 mono-methylation at lysine 20, and H2B ubiquitination at lysine 120. We discuss the normal regulation of these PTMs by the respective "writers" and "erasers" and the impact of their misregulation on genome stability.

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

“…Among the various PTMs, ubiquitination, a covalent attachment of a 76 amino acid protein ubiquitin, is of utmost importance. This PTM regulates a broad spectrum of intracellular processes including molecular biodistribution, protein kinase activity, DNA damage response (DDR), chromatin organization and dynamics, gene expression, cell cycle and death [1][2][3][4][5]. Markedly, through proteasome/lysosome-mediated destruction of key signal transduction regulators, ubiquitination is capable of modulating activities and even shutting down entire signal transduction networks.…”

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

“…DNA methylation is a component of the epigenetic gene-silencing complex, whereas histone (H3 and H4) posttranslational modifications comprise a ubiquitous component of rapid epigenetic changes [9][10][11]. Epigenetic changes are associated with altered transcription.…”

RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

“…12,14 Regulation of transcription through H2Bub1 can occur through recruitment of SWI/SNF complexes, interactions with TFIIS, and, potentially, additional mechanisms. 15 Reduced global levels of H2Bub1 and of RNF20 and RNF40 mRNA, relative to corresponding non-cancerous tissue, were observed in various tumor types, including breast cancer, [16][17][18][19][20][21][22] suggesting that this reduction provides an advantage for tumor growth. Such a reduction could be driven by a variety of mechanisms, including RNF20 promoter hypermethylation 14 or increased expression of pertinent DUBs.…”