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Review
. 2017 Apr;3(4):269-281.
doi: 10.1016/j.trecan.2017.03.006. Epub 2017 Apr 12.

Super-Enhancer-Driven Transcriptional Dependencies in Cancer

Satyaki Sengupta  1 , Rani E George  2
Affiliations
Review

Super-Enhancer-Driven Transcriptional Dependencies in Cancer

Satyaki Sengupta et al. Trends Cancer. 2017 Apr.

Abstract

Transcriptional deregulation is one of the core tenets of cancer biology and is underpinned by alterations in both protein-coding genes and noncoding regulatory elements. Large regulatory elements, so-called super-enhancers (SEs), are central to the maintenance of cancer cell identity and promote oncogenic transcription to which cancer cells become highly addicted. Such dependence on SE-driven transcription for proliferation and survival offers an Achilles heel for the therapeutic targeting of cancer cells. Indeed, inhibition of the cellular machinery required for the assembly and maintenance of SEs dampens oncogenic transcription and inhibits tumor growth. In this article, we review the organization, function, and regulation of oncogenic SEs and their contribution to the cancer cell state.

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Figures

Figure 1
Figure 1. Organization and function of super-enhancers (SEs)
Transcription factor (TF) binding to enhancers (E) results in the recruitment of the Mediator (Med) complex, which facilitates enhancer interaction with the basal transcription machinery and RNA polymerase II (Pol II) at promoters (P) in a gene-specific manner, a process mediated by “looping” of the loaded enhancer to the cognate promoter. Enhancer looping can span large genomic distances (several kb). SEs are characterized by clustering of multiple constituent enhancers (E1–E3) located in close genomic proximity, and distinguished by the presence of multiple TF binding sites and increased density of the Mediator complex. Regular enhancers in neurons and hematopoietic cells are involved in the transcription of housekeeping genes, whereas, SEs regulate only cell-type-specific genes that confer “identity”. Non-lineage-specific genes are silenced in both cell types.
Figure 2
Figure 2. Mechanisms of oncogenic super-enhancer formation
(A) Short insertion mutations that introduce novel MYB binding sites upstream of the TAL1 oncogene, resulting in the formation of a SE that drives TAL1 expression in T-ALL. MYB binding to these de novo sites facilitates SE formation through recruitment of CBP-p300 acetyl-transferase and the TAL1 transcription factor complex, which drive key genes involved in leukemogenesis [38]. (B) SE formation at the LMO1 oncogene in neuroblastoma is contingent upon GATA3 binding at a conserved intronic GATA binding site conferred by the tumorigenic “G” allele. Cells harboring the protective “T” allele (TATA) at this locus have impaired GATA3 binding, leading to diminished recruitment of H3K27Ac, resulting in decreased enhancer activity and greatly reduced LMO1 expression [54]. (C) A chromosomal translocation as found in adenoid cystic carcinoma (ACC) that repositions an unrelated SE in proximity to the MYB oncogene, resulting in its high expression [30]. (D) Focal amplification of SE regions as in lung adenocarcinoma, where a focal amplification ~450s kb downstream of the MYCN locus leads to SE formation and drives high expression of the oncogene [59]. Grey arcs represent physical interactions between SEs and the gene promoter (P).
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