Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4.
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.
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA;
Shawna
S
Guillemette
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA;
Ryan W
RW
Serra
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA;
Min
M
Peng
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA;
Janelle A
JA
Hayes
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
Panagiotis A
PA
Konstantinopoulos
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
Michael R
MR
Green
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA; sharon.cantor@umassmed.edu.
Sharon B
http://orcid.org/0000-0003-2944-6156
SB
Cantor
D001324:Autoantigens / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D024522:Genes, BRCA2 / Q000502:physiology*; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*
D001324:Autoantigens; C115323:CHD4 protein, human; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D002945:Cisplatin
BRCA2; CHD4; DNA repair; hereditary cancer