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Review
. 2018 Jul;75(14):2537-2555.
doi: 10.1007/s00018-018-2820-1. Epub 2018 Apr 24.

Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

Luca Fagnocchi  1 , Vittoria Poli  2 , Alessio Zippo  3   4   5
Affiliations
Review

Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

Luca Fagnocchi et al. Cell Mol Life Sci. 2018 Jul.

Abstract

Cancer heterogeneity arises during tumor progression as a consequence of genetic insults, environmental cues, and reversible changes in the epigenetic state, favoring tumor cell plasticity. The role of enhancer reprogramming is emerging as a relevant field in cancer biology as it supports adaptation of cancer cells to those environmental changes encountered during tumor progression and metastasis seeding. In this review, we describe the cancer-related alterations that drive oncogenic enhancer activity, leading to dysregulated transcriptional programs. We discuss the molecular mechanisms of both cis- and trans-factors in overriding the regulatory circuits that maintain cell-type specificity and imposing an alternative, de-regulated enhancer activity in cancer cells. We further comment on the increasing evidence which implicates stress response and aging-signaling pathways in the enhancer landscape reprogramming during tumorigenesis. Finally, we focus on the potential therapeutic implications of these enhancer-mediated subverted transcriptional programs, putting particular emphasis on the lack of information regarding tumor progression and the metastatic outgrowth, which still remain the major cause of mortality related to cancer.

Keywords: Cancer; Cis-regulatory elements; DNA damage; Enhancer; Epigenetic; Metastasis; Reprogramming; Signaling pathways; Transcription factors; Tumor progression.

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Conflict of interest statement

The authors declare that they have no conflict of interests.

Figures

Fig. 1
Fig. 1
Aberrant activity of transcriptional enhancers favors cancer cell plasticity. a Transcriptional enhancers dictate cell- and tissue-specific transcriptional programs, integrating both lineage-determining and signal-dependent transcription factors. Their activity is constrained by physical limits, such as insulators. b Alteration of the physiological activity of transcriptional enhancers may favor cancer cell plasticity and tumor disruption. Aberrant functionality of both cis- and trans-acting factors converge to impose subverted transcriptional landscapes, which might be favorable for promoting the reprogramming of differentiated cells and induce oncogenic features. Black crosses indicate loss of promoter, enhancer or trans-factors activity; red crosses indicate point mutations in cis-regulatory elements. Curved arrows indicate functional interaction of enhancer regions to cognate promoters. LDTF lineage-determining transcription factors, SDTF signal-dependent transcription factors, RNAPII RNA polymerase II
Fig. 2
Fig. 2
Cis-acting alterations driving oncogenic enhancer activity. a Overview of the possible effects of single-nucleotide polymorphisms and small insertions or deletions on enhancers’ activity. Point mutations may either remove or introduce binding sites at enhancer regions. The following alteration of transcription factor binding leads to enhancer reprogramming, which can cause down-regulation of tumor suppressors or up-regulation of oncogenes (upper and middle panels). Single-nucleotide polymorphisms may also introduce new binding sites in non-enhancer regions, causing nucleation of de novo oncogenic enhancers (lower panel). b Large genomic rearrangements are responsible for enhancers hijacking. Large deletions, translocations, inversions, and copy number alterations can place active enhancers adjacent to proto-oncogenes or remove them from nearby tumor suppression, thus promoting a pro-oncogenic transcriptional program. Black crosses indicate loss of promoter or enhancer activity; red crosses indicate point mutations in cis-regulatory elements. Curved arrows indicate functional interaction of enhancer regions to cognate promoters. Green back slashes indicate the regions affected by large structural variants. SNPs single-nucleotide polymorphisms, INDELs small insertions or deletions, TF transcription factors, RNAPII RNA polymerase II
Fig. 3
Fig. 3
Trans-acting alterations driving oncogenic enhancer activity. a In the intestinal colonic epithelium, WNT pathway activation is responsible for maintaining cell identity. Mutations of multiple factors in the pathway lead to hyper-activation of β-catenin on TCF4-bound enhancer, thus leading to malignant transformation in colorectal cancer cells. b FOXA represents a lineage-determining transcription factor in different tissues. Given its pioneer ability, its mis-regulated DNA binding may favor transcription of oncogenes from oncogenic enhancers (upper panel). Alternatively, its altered ability to recruit other transcription factors or co-factors may promote oncogenic enhancers nucleation (middle and lower panels). c Aberrant methylation landscapes achieved by mutations of DNMTs or TETs represent a major cause of enhancer reprogramming in tumorigenesis. d Three-dimensional structure of the chromatin is favored by helicases and complexes such as mediator and cohesins. Mutations affecting subunits of these multi-protein complexes affects the recruitment of these structural components and the chromatin structure, impairing transcription of tumor suppressors. e In physiological condition, extrinsic and intrinsic stress signals (oxidative, replicative, metabolic, proliferative, and toxic) are sensed and counteracted by specific transcriptional programs. Upon tumorigenesis, new oncogenic signal may affect the activity of transcription factors, such as FOXOs, to activate the DNA-damage response, thus leading on one side to accumulation of DNA damages and on the other side to activation of novel oncogenic enhancers. Black crosses indicate loss of promoter or enhancer activity; red crosses indicate loss of trans-factors activity. Curved arrows indicate functional interaction of enhancer regions to cognate promoters. Colored lightning bolt indicate mutations affecting trans-factors. LDTF lineage-determining transcription factors, SDTF signal-dependent transcription factors, RNAPII RNA polymerase II, TF transcription factors, DDR DNA-damage response
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