Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3741-E3748. doi: 10.1073/pnas.1716029115. Epub 2018 Apr 2.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
2
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
3
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
4
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
5
Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210.
6
Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, TN 37235.
7
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215.
8
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; william_kaelin@dfci.harvard.edu.
10
Howard Hughes Medical Institute, Chevy Chase, MD 20815.

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.

KEYWORDS:

JARID1A; KDM5A; cancer; epigenetics; genetically engineered mouse models

PMID:
29610306
PMCID:
PMC5910822
DOI:
10.1073/pnas.1716029115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center