Downregulation of both mismatch repair and non-homologous end-joining pathways in hypoxic brain tumour cell lines

PeerJ

article

Sophie Cowman¹  Barry Pizer³  Violaine Sée¹ 

[1] Institute of Systems, Molecular and Integrative Biology, Department of Molecular Physiology and Cell Signalling, University of Liverpool;Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah;Paediatric Oncology, Alder Hey Children’s NHS Foundation Trust

关键词: Glioblastoma;    Hypoxia;    DNA repair;    NanoString;    DNA Ligase IV;    PMS2;    HIF inhibition;    Non-homologous end-joining;    Mismatch repair;   

DOI  :  10.7717/peerj.11275

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Glioblastoma, a grade IV astrocytoma, has a poor survival rate in part due to ineffective treatment options available. These tumours are heterogeneous with areas of low oxygen levels, termed hypoxic regions. Many intra-cellular signalling pathways, including DNA repair, can be altered by hypoxia. Since DNA damage induction and subsequent activation of DNA repair mechanisms is the cornerstone of glioblastoma treatment, alterations to DNA repair mechanisms could have a direct influence on treatment success. Our aim was to elucidate the impact of chronic hypoxia on DNA repair gene expression in a range of glioblastoma cell lines. We adopted a NanoString transcriptomic approach to examine the expression of 180 DNA repair-related genes in four classical glioblastoma cell lines (U87-MG, U251-MG, D566-MG, T98G) exposed to 5 days of normoxia (21% O2), moderate (1% O2) or severe (0.1% O2) hypoxia. We observed altered gene expression in several DNA repair pathways including homologous recombination repair, non-homologous end-joining and mismatch repair, with hypoxia primarily resulting in downregulation of gene expression. The extent of gene expression changes was dependent on hypoxic severity. Some, but not all, of these downregulations were directly under the control of HIF activity. For example, the downregulation of LIG4, a key component of non-homologous end-joining, was reversed upon inhibition of the hypoxia-inducible factor (HIF). In contrast, the downregulation of the mismatch repair gene, PMS2, was not affected by HIF inhibition. This suggests that numerous molecular mechanisms lead to hypoxia-induced reprogramming of the transcriptional landscape of DNA repair. Whilst the global impact of hypoxia on DNA repair gene expression is likely to lead to genomic instability, tumorigenesis and reduced sensitivity to anti-cancer treatment, treatment re-sensitising might require additional approaches to a simple HIF inhibition.

【 授权许可】

CC BY