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Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1.

Abstract
Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1(+/-) mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy.
AuthorsWenchu Lin, Jian Cao, Jiayun Liu, Michael L Beshiri, Yuko Fujiwara, Joshua Francis, Andrew D Cherniack, Christoph Geisen, Lauren P Blair, Mike R Zou, Xiaohua Shen, Dan Kawamori, Zongzhi Liu, Chiara Grisanzio, Hideo Watanabe, Yoji Andrew Minamishima, Qing Zhang, Rohit N Kulkarni, Sabina Signoretti, Scott J Rodig, Roderick T Bronson, Stuart H Orkin, David P Tuck, Elizaveta V Benevolenskaya, Matthew Meyerson, William G Kaelin Jr, Qin Yan
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 33 Pg. 13379-86 (Aug 16 2011) ISSN: 1091-6490 [Electronic] United States
PMID21788502 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Histones
  • Men1 protein, mouse
  • Proto-Oncogene Proteins
  • Rbp2 protein, mouse
  • Retinoblastoma Protein
  • Retinol-Binding Proteins, Cellular
  • Histone Demethylases
Topics
  • Animals
  • Enzyme Inhibitors (therapeutic use)
  • Epigenomics
  • Histone Demethylases
  • Histones (metabolism)
  • Methylation
  • Mice
  • Mice, Knockout
  • Neoplasms (enzymology, etiology, prevention & control)
  • Proto-Oncogene Proteins (deficiency)
  • Retinoblastoma Protein (deficiency)
  • Retinol-Binding Proteins, Cellular (antagonists & inhibitors, deficiency)
  • Survival Rate

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