Breast cancer is among the most prevalent tumours affecting women worldwide with death resulting from metastasis. HOTAIR is a long non-coding RNA (lncRNA) situated within the HOXC locus on human chromosome 12q13. High expression of HOTAIR increases breast cancer cell line metastasis and is associated with poor prognosis of breast and other cancers. Transcriptional control of HOTAIR is poorly understood; and the aim of our research is to elucidate this in breast cancer. We developed chromatin state maps from publically available data identifying a putative enhancer element upstream of the HOTAIR gene. We found through the use of chromatin looping assays that the putative enhancer interacts with the canonical and a novel promoter that we identified within the HOXC11 intron. The putative enhancer augmented the activity of both HOTAIR promoters in a luciferase reporter assay, with activity lost upon deletion of highly conserved transcription factor binding sites. Using weighted gene co-expression network analysis (WGCNA) we further highlighted a network of factors associated with the cell cycle, DNA repair and poor prognosis in breast cancer. A key factor within this network was knocked down using siRNA resulting in changes to HOTAIR gene expression. These data conclude that in breast cancer HOTAIR transcriptional regulation involves a complex hub of factors, known to interact, and that this hub may provide a novel biomarker for poor prognosis and reduced survival of breast cancer patients.
Funding provided by the Cancer Council Queensland (AUS) and the National Breast Cancer Foundation.