Review

Epigenetic plasticity and the hallmarks of cancer

See allHide authors and affiliations

Science  21 Jul 2017:
Vol. 357, Issue 6348, eaal2380
DOI: 10.1126/science.aal2380

You are currently viewing the abstract.

View Full Text

Cancer epigenetics in the driver's seat

Recent cancer genome projects unexpectedly highlighted the role of epigenetic alterations in cancer development. About half of human cancers were found to harbor mutations in chromatin proteins. In a Review, Flavahan et al. propose that chromatin and epigenetic aberrations have the potential to confer on cells the full range of oncogenic properties represented in the classic “hallmarks” depiction of cancer. They suggest that genetic, environmental, and metabolic factors can make chromatin aberrantly permissive or restrictive. Permissive chromatin creates a state of “epigenetic plasticity,” which can activate oncogene expression or cell fate changes that drive cancer development.

Science, this issue p. eaal2380

Structured Abstract

BACKGROUND

Chromatin is the essential medium through which transcription factors, signaling pathways, and other cues alter gene activity and cellular phenotypes. It assumes distinct conformations that reinforce regulatory activity or repression at a given locus, and reorganizes in response to appropriate intrinsic and extrinsic signals. The biologist Conrad Waddington famously conceptualized developmental specification as an epigenetic landscape in which differentiating cells proceed downhill along branching canals separated by walls that restrict cell identity. By restricting lineage-specific gene expression and phenotypes, chromatin affects the height of the walls between the canals in this epigenetic landscape.

Genetic, metabolic, and environmental stimuli that disrupt chromatin alter cellular states and responses, thereby predisposing individuals to a range of common diseases. Although cancer is typically considered a genetic disease, chromatin and epigenetic aberrations play important roles in tumor potentiation, initiation, and progression.

ADVANCES

We discuss how the stability of chromatin, or its “resistance” to change, is precisely titrated during normal development, and we propose that deviation from this norm is a major factor in tumorigenesis. We review genetic, environmental, and metabolic stimuli that disrupt the homeostatic balance of chromatin, causing it to become aberrantly restrictive or permissive. Stimuli that increase chromatin resistance may result in a restrictive state that blocks differentiation programs. Stimuli that decrease chromatin resistance may result in a permissive state, which we refer to as epigenetic plasticity. We propose that plasticity allows premalignant or malignant cells to stochastically activate alternate gene regulatory programs and/or undergo nonphysiologic cell fate transitions. Some stochastic changes will be inconsequential “passengers”; others will confer fitness and be selected as “drivers.” As cancer cells divide, acquired epigenetic states may be maintained through cell division by DNA methylation, repressive chromatin, or gene regulatory circuits, giving rise to adaptive epiclones that fuel malignant progression.

We highlight specific chromatin aberrations that confer epigenetic restriction or plasticity, and ultimately drive tumor progression via oncogene activation, tumor suppressor silencing, or adaptive cell fate transitions. Aberrations initiated by defined genetic stimuli, such as chromatin regulator gene mutations, are particularly informative regarding mechanism. Examples include gain-of-function mutations of the Polycomb repressor EZH2 that promote chromatin restriction and hinder differentiation, and metabolic enzyme mutations that disrupt the balance of DNA methylation. Changes in DNA methylation resulting from the latter have been tied to tumor suppressor silencing but may also result in stochastic insulator disruption and oncogene activation. We also carefully consider metabolic and environmental stimuli that disrupt chromatin homeostasis in the absence of genetic changes. Examples include links between folate metabolism and methylase activity, environmental factors that promote DNA hypermethylation in gastrointestinal tissues, and potential effects of microenvironmental stress on chromatin regulator expression. Purely epigenetic mechanisms may explain tumors that arise with few or no recurrent mutations, as well as heterogeneous functional phenotypes within tumors that lack genetic explanation. We conclude that chromatin and epigenetic aberrations can confer wide-ranging oncogenic properties and may fulfill all of cancer’s hallmarks.

OUTLOOK

Initial successes with epigenetic therapies suggest the potential of cancer epigenetics for major clinical impact. Yet realizing this promise will require a clearer understanding of epigenetic mechanisms of tumorigenesis. The identification of increasing numbers of oncogenic epigenetic lesions provides an opportunity to develop and test conceptual and mechanistic models of their functions. Progress will require new technologies for probing chromatin and epigenetic alterations with single-cell precision, as well as experimental models that faithfully recapitulate epigenetic states in tumors. We are optimistic that an improved understanding of epigenetic plasticity and restriction could advance diagnostic strategies for evaluating tumor stage and heterogeneity, and yield new therapeutic strategies for correcting epigenetic lesions or exploiting vulnerabilities of epigenetically altered cells.

Epigenetic plasticity and the hallmarks of cancer.

(Left) Normal chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while facilitating appropriate responses to developmental or environmental cues (blue nuclei represent normal cell state). Genetic, environmental, and metabolic insults that disrupt chromatin can lead to either restrictive or overly permissive chromatin states. (Center) Overly permissive chromatin results in epigenetic plasticity; this plasticity permits stochastic activation of alternate gene regulatory programs (red nuclei represent cancer-like cell state). (Right) Some stochastic changes will be inconsequential “passengers” while others will confer fitness and be selected as “drivers”; in this way, chromatin aberrations have the potential to fulfill each hallmark 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 nonphysiologic cell fate transitions. Whereas many stochastic events will be inconsequential “passengers,” some will confer a fitness advantage to a cell 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.

View Full Text