Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells.
BACKGROUND
The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) have been demonstrated recently to be strong Notch-1 activators. Upregulation of the Notch-1 pathway has been shown to limit growth and suppress hormonal secretion in neuroendocrine (NE) neoplasms. We 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 micromol/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-ADP ribose phosphate was observed.


CONCLUSIONS
VPA and SBHA upregulate Notch-1 effectively, suppress NE 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.
Adler
Joel T
JT
Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, Wis, USA.
Hottinger
Daniel G
DG
Kunnimalaiyaan
Muthusamy
M
Chen
Herbert
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D016716:PC12 Cells / Q000378:metabolism; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; C528828:suberoyl bis-hydroxamic acid; D014635:Valproic Acid