TY - JOUR
T1 - Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase
AU - McBrayer, Samuel K.
AU - Olenchock, Benjamin A.
AU - DiNatale, Gabriel J.
AU - Shi, Diana D.
AU - Khanal, Januka
AU - Jennings, Rebecca B.
AU - Novak, Jesse S.
AU - Oser, Matthew G.
AU - Robbins, Alissa K.
AU - Modiste, Rebecca
AU - Bonal, Dennis
AU - Moslehi, Javid
AU - Bronson, Roderick T.
AU - Neuberg, Donna
AU - Nguyen, Quang De
AU - Signoretti, Sabina
AU - Losman, Julie Aurore
AU - Kaelin, William G.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank members of the W.G.K. and J.-A.L. laboratories at the Dana-Farber Cancer Institute for helpful discussions and the Technical Services staff of the Animal Resources Facility of Dana-Farber Cancer Institute for technical assistance. S.K.M. is supported by postdoctoral fellowship PF-14-144-01-TBE from the American Cancer Society and by a Career Enhancement Project award from the Dana-Farber/Harvard Cancer Center Brain Specialized Program of Research Excellence (SPORE). W.G.K. is a Howard Hughes Medical Institute Investigator and is supported by grants from the NIH.
Funding Information:
We thank members of the W.G.K. and J.-A.L. laboratories at the Dana-Farber Cancer Institute for helpful discussions and the Technical Services staff of the Animal Resources Facility of Dana-Farber Cancer Institute for technical assistance. S.K.M. is supported by postdoctoral fellowship PF-14-144-01-TBE from the American Cancer Society and by a Career Enhancement Project award from the Dana-Farber/Har-vard Cancer Center Brain Specialized Program of Research Excellence (SPORE). W.G.K. is a Howard Hughes Medical Institute Investigator and is supported by grants from the NIH.
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/4/17
Y1 - 2018/4/17
N2 - 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.
AB - 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.
KW - Cancer
KW - Epigenetics
KW - Genetically engineered mouse models
KW - JARID1A
KW - KDM5A
UR - http://www.scopus.com/inward/record.url?scp=85045524429&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045524429&partnerID=8YFLogxK
U2 - 10.1073/pnas.1716029115
DO - 10.1073/pnas.1716029115
M3 - Article
C2 - 29610306
AN - SCOPUS:85045524429
SN - 0027-8424
VL - 115
SP - E3741-E3748
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -