TY - JOUR
T1 - CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma
AU - McKenzie, Lisa D.
AU - LeClair, John W.
AU - Miller, Kayla N.
AU - Strong, Averey D.
AU - Chan, Hilda L.
AU - Oates, Edward L.
AU - Ligon, Keith L.
AU - Brennan, Cameron W.
AU - Chheda, Milan G.
N1 - Funding Information:
Foundation, the Concern Foundation, the Cancer Research Foundation, and the McDonnell Center for Cellular and Molecular Neurobiology of Washington University (awarded to M.G.C.). Additionally, research reported in this publication was supported by the Clinical and Translational Research Funding Program (to M.G.C.) of the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of NIH and The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine (awarded to M.G.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We received additional support from Millipore Sigma in the form of supplies and reagents. J.W.L. is a David Silbert Scholar and H.L.C. is an Amgen Scholar.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Glioblastoma (GBM) is a lethal brain tumour. Despite therapy with surgery, radiation, and alkylating chemotherapy, most people have recurrence within 6 months and die within 2 years. A major reason for recurrence is resistance to DNA damage. Here, we demonstrate that CHD4, an ATPase and member of the nucleosome remodelling and deactetylase (NuRD) complex, drives a component of this resistance. CHD4 is overexpressed in GBM specimens and cell lines. Based on The Cancer Genome Atlas and Rembrandt datasets, CHD4 expression is associated with poor prognosis in patients. While it has been known in other cancers that CHD4 goes to sites of DNA damage, we found CHD4 also regulates expression of RAD51, an essential component of the homologous recombination machinery, which repairs DNA damage. Correspondingly, CHD4 suppression results in defective DNA damage response in GBM cells. These findings demonstrate a mechanism by which CHD4 promotes GBM cell survival after DNA damaging treatments. Additionally, we found that CHD4 suppression, even in the absence of extrinsic treatment, cumulatively increases DNA damage. Lastly, we found that CHD4 is dispensable for normal human astrocyte survival. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, these findings suggest an important resistance mechanism that has therapeutic implications.
AB - Glioblastoma (GBM) is a lethal brain tumour. Despite therapy with surgery, radiation, and alkylating chemotherapy, most people have recurrence within 6 months and die within 2 years. A major reason for recurrence is resistance to DNA damage. Here, we demonstrate that CHD4, an ATPase and member of the nucleosome remodelling and deactetylase (NuRD) complex, drives a component of this resistance. CHD4 is overexpressed in GBM specimens and cell lines. Based on The Cancer Genome Atlas and Rembrandt datasets, CHD4 expression is associated with poor prognosis in patients. While it has been known in other cancers that CHD4 goes to sites of DNA damage, we found CHD4 also regulates expression of RAD51, an essential component of the homologous recombination machinery, which repairs DNA damage. Correspondingly, CHD4 suppression results in defective DNA damage response in GBM cells. These findings demonstrate a mechanism by which CHD4 promotes GBM cell survival after DNA damaging treatments. Additionally, we found that CHD4 suppression, even in the absence of extrinsic treatment, cumulatively increases DNA damage. Lastly, we found that CHD4 is dispensable for normal human astrocyte survival. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, these findings suggest an important resistance mechanism that has therapeutic implications.
UR - http://www.scopus.com/inward/record.url?scp=85062973552&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-40327-w
DO - 10.1038/s41598-019-40327-w
M3 - Article
C2 - 30872624
AN - SCOPUS:85062973552
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 4444
ER -