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CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma.

Scientific reports (2019-03-16)
Lisa D McKenzie, John W LeClair, Kayla N Miller, Averey D Strong, Hilda L Chan, Edward L Oates, Keith L Ligon, Cameron W Brennan, Milan G Chheda
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-RLN3 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Fetal Bovine Serum, USA origin, sterile-filtered, suitable for cell culture, suitable for hybridoma