Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase

Samuel K. McBrayer, Benjamin A. Olenchock, Gabriel J. DiNatale, Diana D. Shi, Januka Khanal, Rebecca B. Jennings, Jesse S. Novak, Matthew G. Oser, Alissa K. Robbins, Rebecca Modiste, Dennis Bonal, Javid Moslehi, Roderick T. Bronson, Donna Neuberg, Quang De Nguyen, Sabina Signoretti, Julie Aurore Losman, William G. Kaelin

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB’s ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/ mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/ mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation.

Original languageEnglish (US)
Pages (from-to)E3741-E3748
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number16
DOIs
StatePublished - Apr 17 2018
Externally publishedYes

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Keywords

  • Cancer
  • Epigenetics
  • Genetically engineered mouse models
  • JARID1A
  • KDM5A

ASJC Scopus subject areas

  • General

Cite this

McBrayer, S. K., Olenchock, B. A., DiNatale, G. J., Shi, D. D., Khanal, J., Jennings, R. B., Novak, J. S., Oser, M. G., Robbins, A. K., Modiste, R., Bonal, D., Moslehi, J., Bronson, R. T., Neuberg, D., Nguyen, Q. D., Signoretti, S., Losman, J. A., & Kaelin, W. G. (2018). Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase. Proceedings of the National Academy of Sciences of the United States of America, 115(16), E3741-E3748. https://doi.org/10.1073/pnas.1716029115