Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4

Genes & Development
Shawna GuillemetteSharon B Cantor

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.

References

Oct 29, 1999·Genes & Development·A J PierceM Jasin
Jun 18, 2002·Science·Niall G HowlettAlan D D'Andrea
Jun 23, 2006·PLoS Genetics·Roland K ChiuBradly G Wouters
Mar 17, 2007·DNA Repair·Alan R LehmannCatherine M Green
Aug 19, 2007·Oncogene·S A Denslow, P A Wade
Oct 26, 2007·Nature·Claude GazinMichael R Green
Feb 12, 2008·Nature·Stacey L EdwardsAlan Ashworth
Nov 20, 2009·Epigenetics : Official Journal of the DNA Methylation Society·Julita Ramírez, James Hagman
May 11, 2010·Nature Structural & Molecular Biology·Peter BouwmanJos Jonkers
Sep 2, 2010·The Journal of Cell Biology·Godelieve SmeenkHaico van Attikum
Sep 2, 2010·The Journal of Cell Biology·Dorthe Helena LarsenJiri Lukas
Nov 12, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jason DolesMichael T Hemann
Nov 12, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kun XieGraham C Walker
Jun 29, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Barbara NorquistElizabeth M Swisher
Jul 2, 2011·Nature·UNKNOWN Cancer Genome Atlas Research Network
Jan 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Siming ZhaoAlessandro D Santin
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
May 24, 2013·Biochemical Society Transactions·Aoife O'Shaughnessy, Brian Hendrich
Aug 21, 2013·Mutation Research·Fintan K T StanleyAaron A Goodarzi
Oct 24, 2014·Annual Review of Medicine·Christopher J LordAlan Ashworth

❮ Previous
Next ❯

Citations

Mar 24, 2016·Cellular Oncology (Dordrecht)·Angelo Ferraro
Jul 23, 2016·Nature·Arnab Ray ChaudhuriAndré Nussenzweig
Aug 25, 2016·Hereditary Cancer in Clinical Practice·Aglaya G Iyevleva, Evgeny N Imyanitov
Aug 9, 2016·Nature Communications·Xia DingShyam K Sharan
Aug 18, 2016·Endocrine-related Cancer·Amélie Fradet-TurcotteAlexandre Orthwein
Aug 24, 2016·Endocrine-related Cancer·Yoko Katsuki, Minoru Takata
Nov 28, 2017·Annual Review of Genetics·Philippe Pasero, Alessandro Vindigni
Feb 24, 2018·Cold Spring Harbor Symposia on Quantitative Biology·Sharon B Cantor, Jennifer A Calvo
May 29, 2018·Cold Spring Harbor Symposia on Quantitative Biology·Whitney L JohnsonDavid Pellman
Aug 30, 2017·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Li-Ya ChiuKyle M Miller
Dec 21, 2017·Expert Review of Anticancer Therapy·Roberto FerraraDavide Melisi
Dec 6, 2018·Biochemical Society Transactions·Darshil R Patel, Robert S Weiss
Jul 6, 2019·EMBO Molecular Medicine·Eliana Mc TacconiMadalena Tarsounas
May 21, 2020·Frontiers in Oncology·Martin LiptaySven Rottenberg
Jul 3, 2020·Nature Reviews. Molecular Cell Biology·Matteo BertiMassimo Lopes
Dec 28, 2018·Genes·Wendy LeungAnja-Katrin Bielinsky
Oct 23, 2018·Annual Review of Cancer Biology·Chun-Chin ChenMaria Jasin
Mar 16, 2019·Scientific Reports·Lisa D McKenzieMilan G Chheda
Apr 9, 2020·Frontiers in Pharmacology·Jiabei ZhouLushan Yu
Aug 21, 2020·Science Signaling·Suhas S KharatShyam K Sharan
Nov 23, 2018·Nature·Yizhou Joseph HeDipanjan Chowdhury
Dec 14, 2018·Molecular & Cellular Oncology·Shabana BegumMartin R Higgs
Nov 1, 2018·EMBO Molecular Medicine·Marta Castroviejo-BermejoVioleta Serra
Nov 7, 2019·Molecular & Cellular Oncology·Manuel Daza-MartinJoanna R Morris
Nov 1, 2020·Nature Reviews. Cancer·Sven RottenbergPaola Perego
Oct 16, 2015·Cancer Discovery·Panagiotis A KonstantinopoulosAlan D D'Andrea
Jan 9, 2021·Expert Opinion on Therapeutic Targets·Sumeet NayakSharon B Cantor
Sep 25, 2020·Gynecologic Oncology·Katherine FuhAlessandro Vindigni
Jul 13, 2020·Seminars in Cell & Developmental Biology·Stephanie TyeJoanna R Morris
Nov 26, 2020·Molecular & Cellular Oncology·Suhas S Kharat, Shyam K Sharan
Feb 9, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·M ChiappaG Damia

❮ Previous
Next ❯

Related Concepts

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.