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.
Highlights
Glioblastoma (GBM) is the most common and aggressive brain tumor[1]
These findings demonstrate that chromodomain helicase DNA binding protein 4 (CHD4) is highly expressed in GBM compared with normal brain and that, within classical GBM, CHD4 expression is associated with poor survival
We show that CHD4 expression correlates with poor patient outcomes, and is a specific vulnerability in brain tumour cells
Summary
Glioblastoma (GBM) is the most common and aggressive brain tumor[1]. Treatment is surgery, radiation and the alkylating chemotherapy, temozolomide. CHD4 promotes the recruitment of DNA methyltransferases to tumour suppressor gene promoters, thereby repressing their expression and promoting tumourigenesis[15]. CHD4 can promote cancer in multiple cell types. CHD4 may be required for DNA repair and cell survival through multiple mechanisms. CHD4 depletion in acute myeloid leukaemia (AML) cell lines increases sensitivity to cytarabine and daunorubicin[23]. These treatment resistance mechanisms are related to the role of CHD4 in DNA damage repair. We set out to explore the relevance of CHD4 to DNA damage response in GBM since DNA damage with radiation and alkylating chemotherapy has been the backbone of GBM treatment for decades
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