WMJ-8-B, a novel hydroxamate derivative, induces MDA-MB-231 breast cancer cell death via the SHP-1-STAT3-survivin cascade

Background and purpose: Histone deacetylase (HDAC) inhibitors have been demonstrate to have broad-spectrum anti-tumour properties and have attracted lots of attention in the field of drug discovery. However, the underlying anti-tumour mechanisms of HDAC inhibitors remain incompletely understood. In this study, we aimed to characterize the underlying mechanisms through which the novel hydroxamate-based HDAC Inhibitor, WMJ-8-B, induces the death of MDA-MB-231 breast Cancer cells.

Experimental approach: Effects of WMJ-8-B on cell viability, cell cycle distribution, Apoptosis and signalling molecules were analysed by the MTT assay, flowcytometric analysis, immunoblotting, reporter assay, chromatin immunoprecipitation analysis and use of siRNAs. A xenograft model was used to determine anti-tumour effects of WMJ-8-B in vivo.

Key results: WMJ-8-B induced Survivin reduction, G2/M cell cycle arrest and Apoptosis in MDA-MB-231 cells. STAT3 phosphorylation, transactivity and its binding to the Survivin promoter region were reduced in WMJ-8-B-treated cells. WMJ-8-B activated the protein Phosphatase SHP-1 and when SHP-1 signalling was blocked, the effects of WMJ-8-B on STAT3 phosphorylation and Survivin levels were abolished. However, WMJ-8-B increased the transcription factor Sp1 binding to the p21 promoter region and enhanced p21 levels. Moreover, WMJ-8-B induced α-tubulin acetylation and disrupted microtubule assembly. Inhibition of HDACs was shown to contribute to WMJ-8-B's actions. Furthermore, WMJ-8-B suppressed the growth of MDA-MB-231 xenografts in mammary fat pads in vivo.

Conclusions and implications: The SHP-1-STAT3-survivin and Sp1-p21 cascades are involved in WMJ-8-B-induced MDA-MB-231 breast Cancer cell death. These results also indicate the potential of WMJ-8-B as a lead compound for treatment of breast Cancer and warrant its clinical development.