GENOMIC ANALYSES AND MECHANISTIC STUDIES TO INVESTIGATE ENHANCER REGULATION IN HYPOXIA

Abstract

Tumor hypoxia is a common phenomenon in solid tumors resulted from inadequate blood supply, and breast cancer is no exception. Hypoxia stimulates angiogenesis, metabolism alteration, invasion and genomic instability, thereby promotes tumor aggressiveness. Clinically, tumor hypoxia is associated with therapeutic resistance and poor patient survival. Breast cancer shows dysregulation of hypoxia target genes, and these genes are often critical in tumor progression. Therefore, there is a need to understand the mechanism of hypoxia regulated gene expression. In this study, we explored genome-wide changes of chromatin landscape in hypoxia and identified putative enhancer for hypoxia target genes. Besides, we studied the TFs and epigenetic regulators enriched at hypoxia-dependent enhancers and promoters, and proposed a possible mechanism regulating transcriptome response to hypoxia. Furthermore, we showed the inhibition of BRDs attenuated hypoxia-induced gene expressions, suggesting the possibility to target tumor hypoxia by disrupting the component of hypoxia-dependent enhancers.