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

2 Citations (Scopus)

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

Fingerprint

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

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase. / McBrayer, Samuel K.; Olenchock, Benjamin A.; DiNatale, Gabriel J.; Shi, Diana D.; Khanal, Januka; Jennings, Rebecca B.; Novak, Jesse S.; Oser, Matthew G.; Robbins, Alissa K.; Modiste, Rebecca; Bonal, Dennis; Moslehi, Javid; Bronson, Roderick T.; Neuberg, Donna; Nguyen, Quang De; Signoretti, Sabina; Losman, Julie Aurore; Kaelin, William G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 16, 17.04.2018, p. E3741-E3748.

Research output: Contribution to journalArticle

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 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, vol. 115, no. 16, pp. E3741-E3748. https://doi.org/10.1073/pnas.1716029115
McBrayer, Samuel K. ; Olenchock, Benjamin A. ; DiNatale, Gabriel J. ; Shi, Diana D. ; Khanal, Januka ; Jennings, Rebecca B. ; Novak, Jesse S. ; Oser, Matthew G. ; Robbins, Alissa K. ; Modiste, Rebecca ; Bonal, Dennis ; Moslehi, Javid ; Bronson, Roderick T. ; Neuberg, Donna ; Nguyen, Quang De ; Signoretti, Sabina ; Losman, Julie Aurore ; Kaelin, William G. / Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 16. pp. E3741-E3748.
@article{4aecae31c22242728c4a8bf77a79c727,
title = "Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase",
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 = "Cancer, Epigenetics, Genetically engineered mouse models, JARID1A, KDM5A",
author = "McBrayer, {Samuel K.} and Olenchock, {Benjamin A.} and DiNatale, {Gabriel J.} and Shi, {Diana D.} and Januka Khanal and Jennings, {Rebecca B.} and Novak, {Jesse S.} and Oser, {Matthew G.} and Robbins, {Alissa K.} and Rebecca Modiste and Dennis Bonal and Javid Moslehi and Bronson, {Roderick T.} and Donna Neuberg and Nguyen, {Quang De} and Sabina Signoretti and Losman, {Julie Aurore} and Kaelin, {William G.}",
year = "2018",
month = "4",
day = "17",
doi = "10.1073/pnas.1716029115",
language = "English (US)",
volume = "115",
pages = "E3741--E3748",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "16",

}

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.

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

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

SN - 0027-8424

IS - 16

ER -