The role of HIF-1α, CBP and p300 in the regulation of Nav1.5 expression in breast cancer cells

Abstract Up-regulation of voltage-gated sodium channels (VGSCs) in breast cancer, especially the cardiac isoform Nav1.5 is correlated with lymph-node metastasis and poor prognosis. In this study, the role of the transcription factor hypoxia inducible factor-1α (HIF-1α) and its co-activators CBP and p300 in regulating Nav1.5 expression in breast cancer cells was investigated. Modulation of HIF-1α expression in MDA-MB-231 (aggressive type) and MCF-7 cells (less aggressive type) was achieved using siRNA targeting HIF-1α and the hypoxia-mimetic agent cobalt chloride (CoCl 2 ), respectively, whereas C646 was used to inhibit CBP and p300 in MDA-MB-231 cells. HIF-1α protein and mRNA of CBP, p300 and Nav1.5 were all expressed at higher levels in MDA-MB-231 cells than in MCF-7 cells. In siHIF-1α–treated MDA-MB-231 cells, Nav1.5, CBP mRNA expression, cell viability and cell migration were all significantly reduced. In CoCl 2 -treated MCF-7 cells, HIF-1α protein expression, CA9, p300 and Nav1.5 mRNA expressions were all increased. Although CoCl 2 caused growth suppression, motility and migration of MCF-7 cells remained intact. Treatment with C646 also successfully inhibited CBP, p300, Nav1.5 mRNA expression followed by suppression of motility and migration in MDA-MB-231 cells. Overall, HIF-1α, CBP and p300 are important transcriptional regulators of Nav1.5 expression in breast cancer.