Epigenetic reprogramming in cancer

Abstract

The demonstration of induced pluripotency and direct lineage conversion has led to remarkable insights regarding the roles of transcription factors and chromatin regulators in mediating cell state transitions. Beyond its considerable implications for regenerative medicine, this body of work is highly relevant to multiple stages of oncogenesis, from the initial cellular transformation to the hierarchical organization of established malignancies. Here, we review conceptual parallels between the respective biological phenomena, highlighting important interrelationships among transcription factors, chromatin regulators, and preexisting epigenetic states. The shared mechanisms provide insights into oncogenic transformation, tumor heterogeneity, and cancer stem cell models.

Figure 1. Developmental specification is associated with global alterations in chromatin structure

A) In pluripotent cells, chromatin is hyper-dynamic and globally accessible. B) Upon differentiation, inactive genomic regions may be sequestered by repressive chromatin enriched for characteristic histone modifications and refractory to regulatory activity. These global structures are regulated by DNA methylation, histone modifications and numerous CRs whose expression levels are dynamically regulated through development. In addition, transcriptional changes are accompanied by focal alterations in chromatin structure at specific gene loci.

Figure 2. Genes involved in both iPS nuclear reprogramming and cancer

List of TFs (A) and CRs (B) implicated in iPS reprogramming together with the malignancies in which they have established roles. These include bona fide oncogenes and tumor suppressors directly affected by genetic alterations as well as other genes with mechanistic roles in cancer.

Figure 3. Cellular hierarchies in normal tissues and malignancies

Normal tissues (left) and a growing list of malignancies (right) have established epigenetic hierarchy, with rare populations of stem cells giving rise to more differentiated cellular progeny through intermediate steps (color shades). Reprogramming experiments have shown that differentiation is reversible (left and right arrows). Cellular transformation (red arrow) is a stepwise process involving accumulation of genetic and epigenetic hits. Once initiated, additional and potentially divergent alterations may occur, establishing a tumor with genetic heterogeneity (illustrated by yellow and green *) and, within each genetic subclone, an epigenetic hierarchy (color shades). Altered activity of key regulators, including CRs and TFs, can play dual roles in cancer, contributing to transformation and epigenetic state transitions (“oncogenic reprogramming”). We speculate that the same network of regulators may then act within the established tumor to rewire differentiated cancer cells into stem-like cells, thus establishing a dynamic equilibrium between differentiation and reprogramming.