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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Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998).
Classon, M. & Harlow, E. The retinoblastoma tumour suppressor in development and cancer. Nat. Rev. Cancer 2, 910–917 (2002).
Knudsen, E. S. & Knudsen, K. E. Tailoring to RB: tumour suppressor status and therapeutic response. Nat. Rev. Cancer 8, 714–724 (2008).
Sherr, C. J. Cancer cell cycles. Science 274, 1672–1677 (1996).
Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Ishak, C. A. et al. An RB-EZH2 complex mediates silencing of repetitive DNA sequences. Mol. Cell 64, 1074–1087 (2016).
Kareta, M. S. et al. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell 16, 39–50 (2015).
Ferrari, R. et al. Adenovirus small E1A employs the lysine acetylases p300/CBP and tumor suppressor Rb to repress select host genes and promote productive virus infection. Cell Host Microbe 16, 663–676 (2014).
Avni, D. et al. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol. Cell 12, 735–746 (2003).
Wells, J., Yan, P. S., Cechvala, M., Huang, T. & Farnham, P. J. Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase. Oncogene 22, 1445–1460 (2003).
Ianari, A. et al. Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell 15, 184–194 (2009).
Cecchini, M. J. & Dick, F. A. The biochemical basis of CDK phosphorylation-independent regulation of E2F1 by the retinoblastoma protein. Biochem. J. 434, 297–308 (2011).
Cecchini, M. J. et al. Loss of the retinoblastoma tumor suppressor correlates with improved outcome in patients with lung adenocarcinoma treated with surgery and chemotherapy. Hum. Pathol. 46, 1922–1934 (2015).
Bosco, E. E. et al. The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J. Clin. Invest. 117, 218–228 (2007).
Witkiewicz, A. K. et al. RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer. Clin. Cancer Res. 18, 5110–5122 (2012).
Kommoss, S. et al. Independent prognostic significance of cell cycle regulator proteins p16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group. Br. J. Cancer 96, 306–313 (2007).
Ludovini, V. et al. Vascular endothelial growth factor, p53, Rb, Bcl-2 expression and response to chemotherapy in advanced non-small cell lung cancer. Lung Cancer 46, 77–85 (2004).
Zhao, W. et al. Altered p16(INK4) and RB1 expressions are associated with poor prognosis in patients with nonsmall cell lung cancer. J. Oncol. 2012, 957437 (2012).
Garsed, D. W. et al. Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer. Clin. Cancer Res. 24, 569–580 (2017).
Knudsen, E. S. et al. Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression. J. Natl Cancer Inst. 104, 1825–1836 (2012).
Sharma, A. et al. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J. Clin. Invest. 120, 4478–4492 (2010).
Burkhart, D. L. & Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat. Rev. Cancer 8, 671–682 (2008).
McNair, C. et al. Differential impact of RB status on E2F1 reprogramming in human cancer. J. Clin. Invest. 128, 341–358 (2017).
Robinson, D. R. et al. Integrative clinical genomics of metastatic cancer. Nature 548, 297–303 (2017).
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 162, 454 (2015).
Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).
Dick, F. A. & Rubin, S. M. Molecular mechanisms underlying RB protein function. Nat. Rev. Mol. Cell Biol. 14, 297–306 (2013).
Kitajima, S. & Takahashi, C. Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation. Cancer Sci. 108, 1726–1731 (2017).
Nicolay, B. N. & Dyson, N. J. The multiple connections between pRB and cell metabolism. Curr. Opin. Cell Biol. 25, 735–740 (2013).
Benevolenskaya, E. V. & Frolov, M. V. Emerging links between E2F control and mitochondrial function. Cancer Res. 75, 619–623 (2015).
Ciavarra, G. & Zacksenhaus, E. Direct and indirect effects of the pRb tumor suppressor on autophagy. Autophagy 7, 544–546 (2011).
Indovina, P., Pentimalli, F., Casini, N., Vocca, I. & Giordano, A. RB1 dual role in proliferation and apoptosis: cell fate control and implications for cancer therapy. Oncotarget 6, 17873–17890 (2015).
Sage, J. The retinoblastoma tumor suppressor and stem cell biology. Genes Dev. 26, 1409–1420 (2012).
Dyson, N. J. RB1: a prototype tumor suppressor and an enigma. Genes Dev. 30, 1492–1502 (2016).
Blanchet, E. et al. E2F transcription factor-1 regulates oxidative metabolism. Nat. Cell Biol. 13, 1146–1152 (2011).
Jones, R. A. et al. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. J. Clin. Invest. 126, 3739–3757 (2016).
Lee, W. H. et al. The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature 329, 642–645 (1987).
Adams, P. D. et al. Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol. Cell. Biol. 19, 1068–1080 (1999).
Carr, S. M., Munro, S., Kessler, B., Oppermann, U. & La Thangue, N. B. Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein. EMBO J. 30, 317–327 (2011).
Munro, S., Khaire, N., Inche, A., Carr, S. & La Thangue, N. B. Lysine methylation regulates the pRb tumour suppressor protein. Oncogene 29, 2357–2367 (2010).
Chan, H. M., Krstic-Demonacos, M., Smith, L., Demonacos, C. & La Thangue, N. B. Acetylation control of the retinoblastoma tumour-suppressor protein. Nat. Genet. 3, 667–674 (2001).
Hirschi, A. et al. An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat. Struct. Mol. Biol. 17, 1051–1057 (2010).
Julian, L. M., Palander, O., Seifried, L. A., Foster, J. E. & Dick, F. A. Characterization of an E2F1-specific binding domain in pRB and its implications for apoptotic regulation. Oncogene 27, 1572–1579 (2008).
Rubin, S. M., Gall, A. L., Zheng, N. & Pavletich, N. P. Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell 123, 1093–1106 (2005).
Calbo, J. et al. G1 cyclin/cyclin-dependent kinase-coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J. Biol. Chem. 277, 50263–50274 (2002).
Liban, T. J. et al. Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family. Proc. Natl Acad. Sci. USA 114, 4942–4947 (2017).
Cecchini, M. J. et al. A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene targeted mice. Mol. Cell. Biol. 34, 2029–2045 (2014).
Dick, F. A. & Dyson, N. pRB contains an E2F1-specific binding domain that allows E2F1-induced apoptosis to be regulated separately from other E2F activities. Mol. Cell 12, 639–649 (2003).
Gubern, A. et al. The N-terminal phosphorylation of RB by p38 bypasses its inactivation by CDKs and prevents proliferation in cancer cells. Mol. Cell 64, 25–36 (2016).
Zhang, J. et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol. Cell 62, 929–942 (2016).
Julian, L. M. et al. Opposing regulation of Sox2 by cell-cycle effectors E2f3a and E2f3b in neural stem cells. Cell Stem Cell 12, 440–452 (2013).
Alabert, C. & Groth, A. Chromatin replication and epigenome maintenance. Nat. Rev. Mol. Cell Biol. 13, 153–167 (2012).
Alabert, C. et al. Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev. 29, 585–590 (2015).
Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).
Blais, A. & Dynlacht, B. D. E2F-associated chromatin modifiers and cell cycle control. Curr. Opin. Cell Biol. 19, 658–662 (2007).
Cook, R. et al. Direct involvement of retinoblastoma family proteins in DNA repair by non-homologous end-joining. Cell Rep 10, 2006–2018 (2015).
Velez-Cruz, R. et al. RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1. Genes Dev. 30, 2500–2512 (2016).
Coschi, C. et al. Haploinsufficiency of an RB-E2F1-Condensin II complex leads to aberrant replication and aneuploidy. Cancer Discov. 4, 840–853 (2014).
Montoya-Durango, D. E. et al. Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins. Mutat. Res. 665, 20–28 (2009).
Chen, J. et al. E2F1 promotes the recruitment of DNA repair factors to sites of DNA double-strand breaks. Cell Cycle 10, 1287–1294 (2011).
Saddic, L. A. et al. Methylation of the retinoblastoma tumor suppressor by SMYD2. J. Biol. Chem. 285, 37733–37740 (2010).
Carnevale, J., Palander, O., Seifried, L. A. & Dick, F. A. DNA damage signals through differentially modified E2F1 molecules to induce apoptosis. Mol. Cell. Biol. 32, 900–912 (2012).
Chong, J. L. et al. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462, 930–934 (2009).
Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 (1996).
Chen, H. Z., Tsai, S. Y. & Leone, G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat. Rev. Cancer 9, 785–797 (2009).
Biedermann, S. et al. The retinoblastoma homolog RBR1 mediates localization of the repair protein RAD51 to DNA lesions in Arabidopsis. EMBO J. 36, 1279–1297 (2017).
Horvath, B. M. et al. Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control. EMBO J. 36, 1261–1278 (2017).
Montoya-Durango, D. E. et al. LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex. BMC Cancer 16, 38 (2016).
Manning, A. L. et al. Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion. Mol. Cell 53, 993–1004 (2014).
Gonzalo, S. et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat. Cell Biol. 7, 420–428 (2005).
Isaac, C. E. et al. The retinoblastoma protein regulates pericentric heterochromatin. Mol. Cell. Biol. 26, 3659–3671 (2006).
Longworth, M. S., Herr, A., Ji, J. Y. & Dyson, N. J. RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev. 22, 1011–1024 (2008).
Woodward, J. et al. Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability. Genes Dev. 30, 2173–2186 (2016).
Lukas, J., Lukas, C. & Bartek, J. More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat. Cell Biol. 13, 1161–1169 (2011).
Mankouri, H. W., Huttner, D. & Hickson, I. D. How unfinished business from S-phase affects mitosis and beyond. EMBO J. 32, 2661–2671 (2013).
Munro, S. et al. Linker histone H1.2 directs genome-wide chromatin association of the retinoblastoma tumor suppressor protein and facilitates its function. Cell Rep 19, 2193–2201 (2017).
Zheng, L., Flesken-Nikitin, A., Chen, P. L. & Lee, W. H. Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability. Cancer Res. 62, 2498–2502 (2002).
Coschi, C. H. et al. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev. 24, 1351–1363 (2010).
Conklin, J. F., Baker, J. & Sage, J. The RB family is required for the self-renewal and survival of human embryonic stem cells. Nat. Commun. 3, 1244 (2012).
Schvartzman, J. M., Sotillo, R. & Benezra, R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat. Rev. Cancer 10, 102–115 (2010).
Sharma, A. et al. Retinoblastoma tumor suppressor status is a critical determinant of therapeutic response in prostate cancer cells. Cancer Res. 67, 6192–6203 (2007).
Varma, H. & Conrad, S. E. Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain. Oncogene 19, 4746–4753 (2000).
Mayhew, C. N. et al. Discrete signaling pathways participate in RB-dependent responses to chemotherapeutic agents. Oncogene 23, 4107–4120 (2004).
Zagorski, W. A., Knudsen, E. S. & Reed, M. F. Retinoblastoma deficiency increases chemosensitivity in lung cancer. Cancer Res. 67, 8264–8273 (2007).
Bourgo, R. J. et al. RB restricts DNA damage-initiated tumorigenesis through an LXCXE-dependent mechanism of transcriptional control. Mol. Cell 43, 663–672 (2011).
Xiao, H. & Goodrich, D. W. The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes. Oncogene 24, 8105–8113 (2005).
The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Branzei, D. & Foiani, M. Regulation of DNA repair throughout the cell cycle. Nat. Rev. Mol. Cell Biol. 9, 297–308 (2008).
Sherr, C. J., Beach, D. & Shapiro, G. I. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov. 6, 353–367 (2016).
Koh, J., Enders, G. H., Dynlacht, B. D. & Harlow, E. Tumor-derived p16 alleles encoding proteins defective in cell cycle inhibition. Nature 375, 506–510 (1995).
Lukas, J. et al. Retinoblastoma-protein-dependent inhibition by the tumor-suppressor p16. Nature 375, 503–506 (1995).
Bruce, J. L., Hurford, R. K. J., Classon, M., Koh, J. & Dyson, N. Requirements for cell cycle arrest by p16INK4a. Mol. Cell 6, 737–742 (2000).
Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).
Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).
Rickman, D. S., Beltran, H., Demichelis, F. & Rubin, M. A. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat. Med. 23, 1–10 (2017).
Bluemn, E. G. et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 32, 474–489 (2017).
The Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).
Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).
Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).
Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003).
Zhou, Z. et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 66, 7889–7898 (2006).
Maddison, L. A., Sutherland, B. W., Barrios, R. J. & Greenberg, N. M. Conditional deletion of Rb causes early stage prostate cancer. Cancer Res. 64, 6018–6025 (2004).
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).
Yun, C. H. et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11, 217–227 (2007).
Pirker, R. Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr. Opin. Oncol. 28, 115–121 (2016).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).
Oser, M. G., Niederst, M. J., Sequist, L. V. & Engelman, J. A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 16, e165–e172 (2015).
George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).
Niederst, M. J. et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6, 6377 (2015).
Rothenberg, S. M. et al. Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways. eLife 4, e06132 (2015).
Ting, D. T. et al. Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science 331, 593–596 (2011).
Liu, Y. et al. Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype. Cell Stem Cell 4, 336–347 (2009).
Akamatsu, S. et al. The placental gene PEG10 promotes progression of neuroendocrine prostate cancer. Cell Rep. 12, 922–936 (2015).
Herrera-Merchan, A. et al. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat. Commun. 3, 623 (2012).
Gonzalez-Vasconcellos, I. et al. Rb1 haploinsufficiency promotes telomere attrition and radiation-induced genomic instability. Cancer Res. 73, 4247–4255 (2013).
Hilgendorf, K. I. et al. The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes Dev. 27, 1003–1015 (2013).
Araki, K., Kawauchi, K., Hirata, H., Yamamoto, M. & Taya, Y. Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization. eLife 2, e01228 (2013).
Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).
The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Ciriello, G. et al. Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163, 506–519 (2015).
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.
Nature Reviews Cancer thanks E. Knudsen, N. La Thangue and S. Mittnacht for their contribution to the peer review of this work.
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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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