Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase.
Proc Natl Acad Sci U S A
; 115(16): E3741-E3748, 2018 04 17.
Article
em En
| MEDLINE
| ID: mdl-29610306
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.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Hipofisárias
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Neoplasias da Glândula Tireoide
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Proteína do Retinoblastoma
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Código das Histonas
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Proteínas de Ligação a DNA
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Histona Desmetilases com o Domínio Jumonji
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Terapia de Alvo Molecular
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Proteínas de Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2018
Tipo de documento:
Article