87 They showed evidence that down-regulation LEE011 nmr in the MSH6 and MLH1 loci is HIF-independent, and associated with Sp1 binding regulated by histone deacetylation.87 Although many different mechanisms are proposed for the repression of MMR genes, these studies support

that hypoxia represses the MMR system, which leads to an increase in displace and frame-shift mutations. For example, intra-tumoral heterogeneity in expression of the MSH3 protein is associated with low levels of microsatellite instability in sporadic colorectal cancers, which can be explained by local hypoxia.103 It is worth mentioning that the frequencies of insertion and deletion mutations, which may be mediated by repression of the MMR system, are high in sporadic cancers including breast, lung, stomach and ovary.48 As discussed earlier, mutations in mitotic spindle check point genes are rare in sporadic human cancers; however, the abnormal expression of these genes is widespread among a variety of human cancers.58 It is possible that hypoxia may alter the expression of mitotic spindle genes and trigger the CIN phenotype in cancer cells. For example, the mitotic spindle checkpoint gene, AURKA (STK15), regulates chromosome segregation during mitosis. Its over expression

results in centrosome amplification and leads to CIN. Over-expression of AURKA is found in breast, Y-27632 chemical structure selleck products colorectal, ovarian, pancreatic, gastric, esophageal, bladder, cervical and head and neck cancers.58 Klein et al. demonstrated that hypoxia (3% O2) quickly up-regulates AURKA at the mRNA and protein levels in hepatocellular carcinoma cells. This up-regulation is HIF1-dependent and mediated by the binding of HIF1 at the HRE

site.104 It would be interesting to determine whether expressions of other mitotic spindle genes, including AURKB, BUB1B, BUB3, CDC20, FZR1, CENPE, CCNB1, NDC80, MAD1L1, MAD2L1, PTTG1, PLK1 and PLK4 are controlled by hypoxia through the HIF1-pathway, because these genes contain putative HRE sites (5′- G/ACGTG-3′) within a 5′ promoter region. A replication fork stalls when it encounters DNA lesions. Prolonged stalling results in the corruption of the replication fork, leading to cell death. Pol ι is one of several DNA polymerases involved in translesion synthesis.105 These polymerases replicate a template regardless of the presence or absence of DNA damage, thus bypassing the lesions. Ito et al. demonstrated that hypoxia (1% O2 for 6 h) up-regulates Pol ι at mRNA and protein levels in cancer cells.47 They also identified a functional HRE element within intron1 of the Pol ι gene, suggesting that up-regulation of Pol ι by hypoxia is HIF1-dependent.47 Among ROS generated during H/R, the hydroxyl radical (OH-) can cleave the bases from DNA and generate simple apurinic/apyrimidinic sites.