UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Date

3-1-2015

Document Type

Article

Medical Subject Headings

Autoantigens; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Female; Genes, BRCA2; Humans; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mutation; Ovarian Neoplasms

Disciplines

Cancer Biology | Cell Biology | Cells | Molecular Genetics | Neoplasms

Abstract

Hereditary cancers derive from gene defects that often compromise DNA repair. Thus, BRCA-associated cancers are sensitive to DNA-damaging agents such as cisplatin. The efficacy of cisplatin is limited, however, by the development of resistance. One cisplatin resistance mechanism is restoration of homologous recombination (HR), which can result from BRCA reversion mutations. However, in BRCA2 mutant cancers, cisplatin resistance can occur independently of restored HR by a mechanism that remains unknown. Here we performed a genome-wide shRNA screen and found that loss of the nucleosome remodeling factor CHD4 confers cisplatin resistance. Restoration of cisplatin resistance is independent of HR but correlates with restored cell cycle progression, reduced chromosomal aberrations, and enhanced DNA damage tolerance. Suggesting clinical relevance, cisplatin-resistant clones lacking genetic reversion of BRCA2 show de novo loss of CHD4 expression in vitro. Moreover, BRCA2 mutant ovarian cancers with reduced CHD4 expression significantly correlate with shorter progression-free survival and shorter overall survival. Collectively, our findings indicate that CHD4 modulates therapeutic response in BRCA2 mutant cancer cells.

Rights and Permissions

Citation: Genes Dev. 2015 Mar 1;29(5):489-94. doi: 10.1101/gad.256214.114. Link to article on publisher's site

Comments

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

Related Resources

Link to Article in PubMed

Keywords

BRCA2, CHD4, DNA repair, hereditary cancer

PubMed ID

25737278

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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