Dysregulation of the basal RNA polymerase transcription apparatus in cancer

• Published in: Nature reviews. Cancer Vol. 13; no. 5; pp. 299 - 314
• Main Authors: Bywater, Megan J., Pearson, Richard B., McArthur, Grant A., Hannan, Ross D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2013; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; DNA-Directed RNA Polymerases - physiology; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic transcription; Humans; Molecular Targeted Therapy; Mutation; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Oncogenes; Physiological aspects; review-article; RNA polymerases; Transcription Factors, General - genetics; Transcription Factors, General - metabolism; Transcriptional Activation - drug effects; Australia
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc3496

Key Points The core RNA polymerase (Pol) subunits and general transcription factors (GTFs) are rarely mutated in cancer, although some GTFs are consistently overexpressed in tumours and this is thought to contribute to malignancy in some cases. Subunits of the mediator complex are increasingly being found to be mutated or amplified in tumours, where they have oncogenic or tumour suppressive activities and functions, depending on the genetic background and cellular context. Regulators of post-initiation stages of transcription, particularly components of RNA Pol II super elongation complexes (SECs), are recurrently mutated in cancer, particularly haematological malignancies through translocation with the mixed lineage leukaemia (MLL) family of transcription factors. The resultant fusion proteins facilitate the enhanced transcription elongation of homeobox (HOX) transcription factors that are involved in embryonic development and haematopoietic cell differentiation, which drives malignancy. RNA Pol I and RNA Pol III are consistently dysregulated in cancer, which is mostly mediated through upstream oncogenic and tumour suppressive signalling pathways rather than through mutations. The most potent and pervasive oncogenic and tumour suppressive components of the transcription apparatus seem to be those that are capable of modulating all three RNA Pols. RNA Pol I transcriptional overactivity has been shown to be necessary for the survival of haematological tumour cells, and the RNA Pol I GTF SL-1 has been successfully targeted using a small-molecule inhibitor to therapeutically treat transgenic mouse models of cancer in vivo . RNA Pol I transcription therapy is currently entering Phase I trials in humans for the treatment of lymphoma and leukaemia. Components of the core transcription apparatus, including the mediator complex and the SEC, represent bone fide therapeutic targets for cancer treatment not only as advanced broad-spectrum cytotoxics but also potentially as part of the new paradigm of personalized medicine. Increasing evidence indicates that components of the RNA polymerase complexes are altered in cancer. This Review discusses how all three classes of human RNA polymerase activity are dysregulated in cancer and the opportunities to therapeutically target RNA polymerase activity. Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein–protein and protein–DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.