Abstract
Tissue hypoxia is now recognized to contribute to the emergence of therapeutic resistance, including radiation-therapy. It has been known that hypoxic stress down-regulates variety of DNA repair gene expressions, but details of DNA-damage responses under hypoxic conditions remains unclear. Here, we tried to clarify details of the molecular mechanism of down-regulations and effects on DNA-damage responses in hypoxic cancer cells.
Hypoxic down-regulations of MLH1, MSH2, MBD4, MRE11A, RAD51, and BRCA1 genes in an oral squamous cell carcinoma cell line, HSC-2, were confirmed by real-time RT-PCR. Their promoter analyses demonstrated that DEC transcriptionally repressed those promoters of the 6 genes via their HDAC-dependent transcriptional activities or physical competitions. Interestingly, hypoxic pre-culture of HSC-2 might delay sensing to DNA damages induced by irradiation and their repair monitored with gH2AX. Importantly, those altered responses to DNA damage in hypoxia-pretreated cells affected radiation sensitivity that was recovered by knock down of DEC2.
These results suggest that the HIF-1-DEC system may play an important role in DNA damage responses, relating to anticancer therapies and protections against radiation exporsure, via transcriptional regulations in hypoxic cells.
