Hypoxia: Impact on genetic instability, DNA repair, gene silencing, and therapeutic resistance.
In the mid 1990's, we developed the hypothesis that the hypoxic tumor microenvironment could be a cause of genetic instability in cancer. This was contrary to the dogma at the time, because it was thought that under hypoxia there would be less oxidative damage to DNA. We showed that growth of cancer cells in vivo in tumor xenografts produces an elevated mutation rate compared to growth of the same cells in culture (Reynolds, Cancer Res. 1996), and we went on to demonstrate that this effect could be attributed to hypoxia. Since then, we have systematically dissected the mechanisms underlying this effect. These mechanisms include transcriptional downregulation of the homology-dependent repair genes RAD51 and BRCA1 (Bindra, Cancer Res. 2006), of the Fanconi pathway gene FANCD2 (Scanlon, Molecular Cancer Res. 2014) and of the mismatch repair gene, MLH1 (Mihaylova, Mol. Cell. Biol. 2003) plus induction of microRNAs 210 and 373 that suppress expression of several DNA repair factors (Crosby, Cancer Res. 2009). In addition, besides acute transcriptional downregulation, our laboratory discovered that hypoxia promotes silencing of the DNA repair genes, BRCA1 and MLH1, in a pathway that is dependent on the histone lysine demethylase, LSD-1 (Lu, Mol. Cell. Biol. 2011 and Lu, Cell Reports 2014).