Core regulatory circuitries in defining cancer cell identity across the malignant spectrum
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- BIRMINGHAM CITY UNIVERSITY
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
- Departments of Cardiology, Sandwell and West Birmingham Hospitals NHS Trust and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
- Institute of Cancer and Genomic Sciences
- Mammalian Genetics Unit, Medical Research Council Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK.
- Medical Research Council (MRC) Harwell Institute
- Oxfordshire Clinical Commissioning Group
- MRC Health Data Research UK
- NIHR Experimental Cancer Medicine Centre
- NIHR Surgical Reconstruction and Microbiology Research Centre
- NIHR Biomedical Research Centre
- Harvard Medical School
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 triggers 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 re-purposing 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.
|Publication status||Published - 8 Jul 2020|