Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells

作者：Adler Joel T; Hottinger Daniel G; Kunnimalaiyaan Muthusamy; Chen Herbert^*

来源：Surgery, 2008, 144(6): 956-961.

DOI：10.1016/j.surg.2008.08.027

Background. The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) have been demonstrated recently to be strong Notch-l activators. Upregulation of the Notch-1 pathway has been shown to limit growth and suppress hormonal secretion in neuroendocrine (NE) neoplasms. Vile hypothesized that HDAC inhibition would be an effective strategy to activate the Notch-1 pathway and inhibit growth and hormonal secretion in pheochromocytoma cells.
Methods. Pheochromocytoma PC-12 cells were treated with up to 8 mmol/L VPA or 40 mu mol/L SBHA for 2 days. NE tumor markers achaete-scute complex-like 1 (ASCL1) and chromogranin A (CgA) were measured by Western analysis after treatment. Growth was assessed by a cellular proliferation assay; Western analysis was used to determine the mechanism of growth regulation.
Results. HDAC inhibitor treatment caused a dose dependent decrease in ASCL1 and CgA while increasing the amount of active Notch-1 protein; with a 6-day treatment, dose-dependent growth inhibition and cleavage of the apoptotic markers caspase-3 and poly-ADPribose phosphate was observed.
Conclusion. VPA and SBHA upregulate Notch-1 effectively, suppress ATS tumor markers, and decrease growth via apoptosis of pheochromocytoma cells in vitro. Activation of the Notch-1 signaling pathway with HDAC inhibitors may represent a new strategy for treating pheochromocytomas. (Surgery 2008; 144:956-62.)

• 出版日期2008-12