The epigenetic regulation of HIF-1α by SIRT1 in MPP+ treated SH-SY5Y cells

Both silent information regulator 1 (SIRT1) and hypoxia inducible factor 1 (HIF-1) have been found to play important roles in the pathophysiology of Parkinson's disease (PD). However, their mechanisms and their relationship still require further study. In the present study, we focused on the change and relationship of SIRT1 and HIF-1 alpha in PD. PD cell models were established by using methyl-4-phenylpyridinium (MPP+), which induced inhibition of cell proliferation, cell cycle arrest and apoptosis. We found that the expression of HIF-1 alpha and its target genes VEGFA and LDHA increased and that SIRTI expression was inhibited in MPP+ treated cells. With further analysis, we found that the acetylation of H3K14 combined with the HIF-1 alpha promoter was dramatically increased in cells treated with MPP+, which resulted in the transcriptional activation of HIF-1 alpha. Moreover, the acetylation of H3K14 and the expression of HIF-1 alpha increased when SIRT1 was knocked down, suggesting that SIRTI was involved in the epigenetic regulation of HIF-1 alpha. At last, phenformin, another mitochondrial complex1 inhibitor, was used to testify that the increased HIF-1 alpha was not due to off target effects of MPP+. Therefore, our results support a link between PD and SIRT1/H1F-1 alpha signaling, which may serve as a clue for understanding PD. (C) 2016 Elsevier Inc. All rights reserved.