Research SummaryHypoxia-mediated expansion of transcriptome due to epigenetic modifications in breast cancer tumorigenesis and chemoresistance
In the post-genomic era, alternative splicing is receiving increasing attention as a major mechanism of transcriptome/proteome expansion. It is estimated that more than 90% of human genes undergo alternative splicing in a cell and tissue-specific manner during normal development. The alternations in signaling pathways can be sensed by both splicing and epigenetics machinery and may result in aberrant alternative splicing in cancer. Among the signaling pathways, Hypoxia-induced response plays a key role in the progression of Triple-Negative Breast Cancer (TNBC) and is considered as one of the hallmarks of TNBC. Hypoxia promotes an adaptive transcription response resulting in epigenetic changes which support cancer cell growth. Considering that epigenetic modifications are known to regulate alternative splicing, and epigenetics plays a crucial role in cellular response to hypoxia, it is possible that hypoxia-induced response contributes to cancer-specific alternative spliced transcripts due to epigenetic changes. However, the interplay between hypoxia and alternative splicing is largely unexplored in TNBC. In this project, we are investigating whether and how hypoxia contributes to the generation of cancer-specific spliced isoforms via epigenetic modifications and whether hypoxia-induced alternative splicing is involved in the tumorigenesis of TNBC.
Figure Legend: Schematic illustrating hypothetical model of Hypoxia-induced alternative splicing in cancer. The stabilization of HIF-1alpha under hypoxic condition in cancer cells may cause deregulation of epigenetic modifiers, which can then lead to changes in epigenetic modifications at or near the alternative exons, resulting in cancer-specific splicing.