Targeting super-enhancer activity for colorectal cancer therapy

Abstract

In addition to genetic variants and copy number alterations, epigenetic deregulation of oncogenes and tumor suppressors is a major contributor in cancer development and propagation. Regulatory elements for gene transcription regulation can be found in promoters which are located in the vicinity of transcription start sites but also at a distance, in enhancer sites, brought to interact with proximal sites when occupied by enhancer protein complexes. These sites provide most of the specific regulatory sequences recognized by transcription factors. A subset of enhancers characterized by a longer structure and stronger activity, called super-enhancers, are critical for the expression of specific genes, usually associated with individual cell type identity and function. Super-enhancers show deregulation in cancer, which may have profound repercussions for cancer cell survival and response to therapy. Dysfunction of super-enhancers may result from multiple mechanisms that include changes in their sequence, alterations in the topological neighborhoods where they belong, and alterations in the proteins that mediate their function, such as transcription factors and epigenetic modifiers. These can become potential targets for therapeutic interventions. Genes that are targets of super-enhancers are cell and cancer type specific and could also be of interest for therapeutic targeting. In colorectal cancer, a super-enhancer regulated and over-expressed oncogene is MYC, under the influence of the WNT/β-catenin pathway. Identification and targeting of additional oncogenes regulated by super-enhancers in colorectal cancer may pave the way for combination therapies targeting the super-enhancer machinery and signal transduction pathways that regulate the specific transcription factors operative on them.

Therapeutic opportunities for hypermutated urothelial carcinomas beyond immunotherapy

“…Moreover, several genes encoding for proteins of the DNA damage response (DDR) are mutated in a significant proportion of these cancers, including BRCA2 (22.6%), ATM (25.5%) and POLQ (21.7%). DDR following double strand breaks is particularly active in areas of the genome with high transcriptional activity, where the epigenetic machinery associated with transcription is also a key player that unwinds chromatin, dislocates or removes histone octamers and provides the epigenetic marks for recruitment of transcription factors and the general transcription machinery [ 7 ]. ARID1A mutations are associated with MMR defects and with response to immune checkpoint inhibitors [ 8 ].…”