Enhancer deregulation in cancer and other diseases

Abstract

Summary Mutations in enhancer-associated chromatin-modifying components and genomic alterations in non-coding regions of the genome occur frequently in cancer and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin-modifying factors might affect enhancer activity of disease-relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions or deletions but also larger genomic rearrangements such as duplications, deletions, translocations and inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer-regulated and disease-relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues.

Potential application of cell reprogramming techniques for cancer research

“…Transcriptional enhancers are enriched for the binding of chromatin factors such as p300/CBP, a major histone acetyltransferase that mediates the formation of H3K27AC, and its mediator, a long-range interaction facilitator [157]. The correct ordering and functional integrity of these modifiers with transcription factors and enhancers should be clarified in terms of the generation and expansion of CSCs [158]. …”

Targeting human SET1/MLL family of proteins

“…Other MLL family members have also been implicated in disease . The human SET1 family of proteins includes MLL1 (KMT2A), MLL2 (KMT2D), MLL3 (KMT2C), MLL4 (KMT2B), SET1A (KMT2F), and SET1B (KMT2G).…”

From Anti-EBV Immune Responses to the EBV Diseasome via Cross-reactivity

“…KMT2C not only may act as a tumor suppressor in leukemias and T-cell lymphomas, 75,76 but it is also implicated in bladder, breast, colorectal, endometrial, gastric, head and neck, lung, and liver cancer, and in medulloblastoma. 108 Then, in spite of the lack of space, it is mandatory noting the harmful cross-reactivity platform represented by the peptide commonality between the immunoreactive EBV epitopes and Wiskott-Aldrich syndrome protein (WASP) (►Table 4). The 29 pentapeptides shared with EBV epitopes mainly occur throughout the central and COOH regulatory domains of the WASP primary sequence (►Fig.…”