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

McBrayer SK, Olenchock BA, DiNatale GJ, Shi DD, Khanal J, Jennings RB, Novak JS, Oser MG, Robbins AK, Modiste R, Bonal D, Moslehi J, Bronson RT, Neuberg D, Nguyen QD, Signoretti S, Losman JA, Kaelin WG
Proc Natl Acad Sci U S A. 2018 115 (16): E3741-E3748

PMID: 29610306 · PMCID: PMC5910822 · DOI:10.1073/pnas.1716029115

Inactivation of the retinoblastoma gene () 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 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 deletion significantly impedes tumorigenesis in 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 mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established -null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by inactivation.

MeSH Terms (21)

Alleles Animals DNA-Binding Proteins Echocardiography Enzyme Activation Fibroblasts Genes, Retinoblastoma Heart Septal Defects Histone Code Integrases Jumonji Domain-Containing Histone Demethylases Mice Mice, Inbred C57BL Molecular Targeted Therapy Neoplasm Proteins Pituitary Neoplasms Recombinant Fusion Proteins Retinoblastoma Protein Tamoxifen Thyroid Neoplasms Transgenes

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