Department of Molecular, Cell and Cancer Biology
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
Cancer Biology | Cell Biology | Cells | Molecular Genetics | Neoplasms
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.
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Citation: Genes Dev. 2015 Mar 1;29(5):489-94. doi: 10.1101/gad.256214.114. Link to article on publisher's site
BRCA2, CHD4, DNA repair, hereditary cancer
Guillemette, Shawna S.; Serra, Ryan W.; Peng, Min; Hayes, Janelle A.; Konstantinopoulos, Panagiotis A.; Green, Michael R.; and Cantor, Sharon B., "Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4" (2015). Molecular, Cell and Cancer Biology Publications. 12.
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