Cancer epigenetic mechanisms support the acquisition of hallmark characteristics during oncogenesis. EZH2 - an important histone methyltransferase that writes histone H3 lysine 27 trimethylation marks - is known to be dysregulated in cancer cells. However, the interactions between EZH2 and miRNAs that form a complex network of cross-talk and reciprocal regulation that enable cancer cells to acquire hallmark characteristics have been relatively poorly appreciated. The specific functions of EZH2 appear to be regulated by a vast array of miRNAs, which direct EZH2 toward regulation over the development of specific hallmark characteristics. This review discusses recent advances in the understanding of EZH2, focusing on its collaboration with miRNAs to orchestrate oncogenesis. These epigenetic processes promote the evasion of apoptosis/cell cycle arrest, cellular dedifferentiation and the establishment of a tumor microenvironment that facilitates local cancer cell invasion, anti-cancer drug resistance and evasion of the immune response.
Keywords: DNA methylation; EZH2; epigenetics; histone modification; miRNAs; tumor microenvironment.
Cancer epigenetics involves cellular processes that ensure that gene expression changes that enable cancer cells to outcompete their neighboring normal tissues are passed on from one cancer cell to the next. One key epigenetic player is called EZH2, which is an enzyme that transfers methyl (CH3) groups from donor molecules to the histone proteins around which DNA is coiled. The transfer of methyl groups to histones – a process called histone methylation – silences the production of proteins from the genes coded in DNA. To achieve this goal, EZH2 is directed to affect specific genes through interactions with other molecules consisting of short sequences of RNA (a molecule similar in structure to DNA). The specific RNA molecules in question are called miRNAs or non-coding RNAs. These EZH2/miRNA interactions form a complex web of circuits that enables cancer cells to gain characteristics that give them a competitive advantage over their normal tissue neighbors. This review discusses recent advances in the understanding of the role of EZH2 in cancer formation, focusing on the interactions it has with miRNAs (and other non-coding RNAs) to organize many different processes linked with cancer formation. These processes include the avoidance of cell death or cell growth arrest, the development of stem cell properties and the formation of an environment around tumor cells that allows them to invade adjacent normal tissue (i.e., metastasize) and avoid being killed by anti-cancer drugs and the immune system.