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OPINION

Non-canonical functions of the RB protein in cancer

Nature Reviews Cancer volume 18, pages 442–451 (2018)Cite this article

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Abstract

The canonical model of RB-mediated tumour suppression developed over the past 30 years is based on the regulation of E2F transcription factors to restrict cell cycle progression. Several additional functions have been proposed for RB, on the basis of which a non-canonical RB pathway can be described. Mechanistically, the non-canonical RB pathway promotes histone modification and regulates chromosome structure in a manner distinct from cell cycle regulation. These functions have implications for chemotherapy response and resistance to targeted anticancer agents. This Opinion offers a framework to guide future studies of RB in basic and clinical research.

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Fig. 1: Canonical RB–E2F regulation and mechanisms of CDK resistance.
Fig. 2: Roles for RB in genome stability and regulation of chromatin.
Fig. 3: Proposed model for RB1 loss in transdifferentiation and drug resistance.
Fig. 4: Features of the canonical and non-canonical RB pathways.

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Acknowledgements

Research in the authors’ laboratories is supported by the US National Institutes of Health (R01 CA207757 and R21 CA179907 to D.W.G., R21 AG050296 and R01 CA114102 to J.S. and R01 GM117413 to N.J.D.) and the Canadian Institutes of Health Research (MOP-89765 and MOP-64253 to F.A.D.). F.A.D. is the Wolfe Senior Fellow in Tumour Suppressor Genes at Western University. J.S. is the Harriet and Mary Zelencik Scientist in Children’s Cancer and Blood Diseases.

Reviewer information

Nature Reviews Cancer thanks E. Knudsen, N. La Thangue and S. Mittnacht for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. London Regional Cancer Program, Children’s Health Research Institute, Western University, London, Ontario, Canada

    Frederick A. Dick

  2. London Regional Cancer Program, Department of Biochemistry, Western University, London, Ontario, Canada

    Frederick A. Dick

  3. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

    David W. Goodrich

  4. Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA

    Julien Sage

  5. Massachusetts General Hospital Cancer Center, Laboratory of Molecular Oncology, Harvard Medical School, Charlestown, MA, USA

    Nicholas J. Dyson

Authors
  1. Frederick A. Dick
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  2. David W. Goodrich
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  3. Julien Sage
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  4. Nicholas J. Dyson
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Contributions

F.A.D., J.S. and D.W.G. researched data for the article, provided substantial contribution to the discussion of content, wrote the manuscript and reviewed and/or edited the manuscript before submission. N.J.D. provided substantial contribution to the discussion of content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Frederick A. Dick.

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Dick, F.A., Goodrich, D.W., Sage, J. et al. Non-canonical functions of the RB protein in cancer. Nat Rev Cancer 18, 442–451 (2018). https://doi.org/10.1038/s41568-018-0008-5

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