Core regulatory circuitries in defining cancer cell identity across the malignant spectrum

Jahangiri, Leila and Tsaprouni, Loukia and Trigg, Ricky M and Williams, John A and Gkoutos, Georgios V and Turner, Suzanne D and Pereira, Joao (2020) Core regulatory circuitries in defining cancer cell identity across the malignant spectrum. Open Biology, 10 (7). ISSN 2046-2441

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Gene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors create and engage super-enhancers by recruiting acetylation writers depositing permissive H3K27ac chromatin marks. These super- enhancers are largely associated with BET proteins, including BRD4 that influence higher- order chromatin structure. The orchestration of these events trigger accessibility of RNA polymerase machinery and the imposition of lineage-specific gene expression. In cancers, CRCs drive cell identity by superimposing developmental programmes on a background of genetic alterations. Further, the establishment and maintenance of oncogenic states are reliant on CRCs that drive factors involved in tumour development. Hence, the molecular dissection of CRC components driving cell identity and cancer state can contribute to elucidating mechanisms of diversion from pre-determined developmental programmes and highlight cancer dependencies. These insights can provide valuable opportunities for identifying and repurposing drug targets. In this article, we review the current understanding of CRCs across solid and liquid malignancies and avenues of investigation for drug development efforts. We also review techniques used to understand CRCs and elaborate the indication of discussed CRC transcription factors in the wider context of cancer CRC models.

Item Type: Article
Identification Number:
19 June 2020Accepted
8 July 2020Published Online
Uncontrolled Keywords: super-enhancers, liquid and solid cancers, cell identity, core regulatory circuitry
Subjects: CAH01 - medicine and dentistry > CAH01-01 - medicine and dentistry > CAH01-01-01 - medical sciences (non-specific)
Divisions: Faculty of Health, Education and Life Sciences > School of Health Sciences
Depositing User: Leila Jahangiri
Date Deposited: 26 Jun 2020 14:45
Last Modified: 03 Mar 2022 15:37

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