Epigenetic plasticity and the hallmarks of cancer

Abstract

Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states, while also facilitating appropriate responses to developmental or environmental cues. Genetic, environmental or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or ‘plastic’ states may allow stochastic oncogene activation or non-physiologic cell fate transitions. While many stochastic events will be inconsequential ‘passengers’, some will confer fitness and be selected as ‘drivers’. We review the broad roles played by epigenetic aberrations in tumor initiation and evolution, and their potential to give rise to all classic hallmarks of cancer.

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

“…Modulation of chromatin structure due to post-translational modification of histones plays a key role in establishing cell type-specific gene expression patterns and alterations of this process are involved in tumorigenesis (Flavahan et al, 2017). Frequent mutations of genes encoding for chromatin modifying enzymes and histones in multiple human cancer types further emphasize the role of perturbed epigenetic programs in tumor evolution (Feinberg et al, 2016).…”

Limited mutagenicity of electronic cigarettes in mouse or human cells in vitro

“…Whereas genotoxicity is a key determinant of carcinogenicity [77], nongenotoxic modes of action, including epigenetic effects, such as aberrant DNA methylation, histone modifications, chromatin remodeling, and micro-RNA derived modulation of gene expression, are alternative or complementary mechanisms of carcinogenesis [78–86]. Future investigations are needed to determine whether e-cig vapor may exert epigenetic effects of relevance to carcinogenesis.…”

Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

“…Previous studies have shown that tumors exhibit both genetic and epigenetic heterogeneity within cell populations, and that epigenetic changes, such as DNA methylation and/or histone modifications, accumulate in the genome throughout oncogenesis (12)(13)(14)(15). This dynamic landscape may permit the introduction of adaptive ALK-independent mechanisms of drug resistance within targeted cells.…”

“…HDAC inhibitors may profoundly alter the activity of enhancers, the key DNA elements that regulate cell-specific gene expression, and thereby significantly influence the transcription of genes involved in the drug response (14,17,18).…”