Role of NSD1 in H2O2-induced GSTM3 suppression.

Abstract Nuclear receptor-binding SET domain-containing protein 1 (NSD1) has been proved to act as a histone methyltransferase and a transcription co-factor to regulate gene expression. However, the role of NSD1 in oxidative stress remains poorly understood. In the present study, we focused on the NSD1 regulation of antioxidant enzyme gene glutathione S-transferase M3 ( GSTM3 ) expression in response to oxidative stress. H 2 O 2 treatment caused the decrease of both NSD1 and GSTM3 expression, and the depletion of NSD1 expression by specific siRNA reversed the H 2 O 2 -reduced GSTM3 expression. Furthermore, we investigated NSD1 modulating the transcription of GSTM3 promoter with − 63A/C polymorphism closed to TATA box in response to H 2 O 2 by luciferase and in vitro or in vivo DNA–protein binding assays. The promoter activity of GSTM3 with − 63A was higher than − 63C, and was increased or decreased by the overexpression or depletion of NSD1, but − 63C was not influenced. H 2 O 2 repressed the promoter activity of GSTM3 with − 63A more than − 63C, and the depletion of NSD1 expression weakened H 2 O 2 inhibition on the − 63A promoter, but augmented H 2 O 2 inhibition on the − 63C promoter. In addition, NSD1 interacted with RNAPII and bound to GSTM3 − 63A/C TATA box, with higher binding affinity to − 63A than to − 63C. These data indicated that NSD1 implicated in H 2 O 2 -induced oxidative stress, and H 2 O 2 -induced NSD1 suppression resulted in the decrease of GSTM3 expression through the − 63A/C TATA box.