SGI-1027 Small Molecule Inhibits DNMT and Promotes p21-Mediated Apoptosis via Epigenetic Alterations in SK-N-SH Neuroblastoma Cells

SGI-1027 Small Molecule Inhibits DNMT and Promotes p21-Mediated Apoptosis via Epigenetic Alterations in SK-N-SH Neuroblastoma Cells

Alvin Sherman Library

Neuroblastoma is an aggressive childhood cancer originating from neural crest cells. Treatment for high-risk neuroblastoma includes chemotherapy. Emerging evidence indicates that DNMT inhibitor codenamed SGI-1027 may facilitate cell cycle arrest and induce apoptosis by modulating cell cycle regulatory pathways. Therefore, we hypothesize that SGI-1027 treatment could lead to apoptosis mediated cell death in SK-N-SH cells through the upregulation of p21 transcription.

This study investigated whether SGI-1027, a DNA methyltransferase inhibitor, causes DNA methylation and upregulation of p21 through a p53-independent pathway, which could lead to cell cycle arrest and intrinsic-pathway mediated apoptosis in SK-N-SH cells. To assess the effects of SGI-1027, we conducted qRT-PCR experiments, to evaluate the DNMT-3A, and DNMT-3B gene expression levels. Also, we performed western blot analyses to examine the key proteins of cell cycle and apoptosis regulation, including p21, p53, Tri-Methyl-histone H3, Tri-Methyl-histone H4, BAX, and BCL-XL.

qRT-PCR results revealed a significant downregulation of DNMT-3A and 3B expression in the SGI1027 treated group compared to the control. Western blot analysis revealed that SGI-1027 elevates p21 levels significantly in a p53-independent manner and induces apoptosis through elevation of BAX and downregulation of BCL-XL.

In conclusion, our study suggests that SGI-1027 could induce apoptosis in neuroblastoma cells through p21 upregulation with simultaneous increase in BAX levels. If validated further using in vivo studies, DNMT-targeted therapies could represent a significant advancement in developing new treatments for aggressive cancers.

(This project was supported by the National Pediatric Cancer Foundation (NPCF), and The Royal Dames of Cancer Research Inc. Ft. Lauderdale, Florida)