Gene enhancer deregulation and epigenetic vulnerability

Abstract

One major goal of cancer research is to identify tumor-specific mechanisms that sustain cell proliferation or survival and to develop the corresponding therapies that target selectively against tumor. Recent sequencing of primary tumor samples supports that aberration of chromatin modification and epigenetic states plays a central role in oncogenesis. For example, mutation of DNA methyltransferase 3A (DNMT3A, Figure 1) occurs in approximately 20-30% of acute myeloid leukemia (AML) and 5-15% of other hematological malignancies and disorders, making DNMT3A one of the most frequently mutated genes in blood cancer [1]; genes encoding chromatin-remodeling protein complexes are found recurrently mutated or deleted in various tumors. Thus, DNMT3A and ATP-dependent chromatin remodelers appear to function as tumor suppressors, most likely, in a context-dependent manner. However, it remains elusive how alteration of chromatin-modifying machineries contributes to tumorigenesis, and mechanism-based therapeutic approaches are to be developed. Chromatin modifications ensure distinctive cellular identities. Past studies have shed light on several principles in chromatin modifications. One important property is reversibility. Epigenomic states are reset in response to developmental or environmental cues such as differentiation. Epigenetic changes are mediated by antagonizing enzymes that ‘write’ or ‘erase’ specific chromatin modification, exemplified by DNA methyltransferase or demethylase, and histone acetyltransferase (HAT) or deacetylase (HDAC). Second, epigenetic states can be relatively stable over cell divisions. Such ‘inheritance’ is partly owing to self-recruitment of modifying enzymes to promote self-propagation. Furthermore, different chromatin modifications that fall into the same gene-active or gene-repressive category often cooperate forming a selfreinforcement network. For example, methylated DNA is ‘read’ by MeCP2, which recruits HDACs to deacetylate histones (Figure 1). Due to the epigenetic crosstalk via antagonizing and reinforcing networks, one would Editorial