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Suberoylanilide Aydroxamic Acid (Saha) Activates Notch1 Signaling and Inhibits Proliferation By Inducing Cell Cycle Arrest in Carcinoid Tumor Cells
David Y. Greenblatt*, Max Cayo, Abram Vaccaro, Muthusamy Kunnimalaiyaan, Herbert Chen
Department of Surgery, University of Wisconsin, Madison, WI

Background: Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor that has shown anti-tumor effects in vitro and in vivo and is in clinical trials for a variety of malignancies. To date, the effect of SAHA in carcinoid cancers has not been characterized. In this study we analyzed the effects of SAHA on cell growth in two carcinoid tumor cell lines.
Methods: Human gastrointestinal (BON) and bronchopulmonary (H727) carcinoid cells were treated with SAHA in concentrations from 1 to 50 μM for up to 4 days. Whole cell extracts were analyzed by immunoblotting for evidence of histone acetylation and activation of Notch1, an important neuroendocrine signaling molecule. The MTT rapid colorimetric assay was used to assess the effect of SAHA on carcinoid cell growth. Western blots were performed using antibodies against the cyclin-dependent kinase inhibitors p21 and p27, as well as the cell cycle promoter cyclin D1, to look for evidence of cell cycle arrest.
Results: SAHA treatment of BON and H727 carcinoid tumor cells resulted in increased expression of acetylated histone 4, indicating HDAC inhibition. Furthermore, SAHA treatment led to a dose-dependent induction of the neuroendocrine signaling protein Notch1 in both its full-length and active, cleaved forms. Achaete-scute complex-like 1 (ASCL1), a downstream target of Notch1 signaling known to regulate the neuroendocrine phenotype, was suppressed by SAHA. Carcinoid tumor cell proliferation was inhibited by the drug in a dose-dependent manner. The mechanism of growth inhibition was G1 cell cycle arrest, as evidenced by increased protein levels of p21 and p27, and suppression of cyclin D1, in SAHA-treated cells.
Conclusions: We report for the first time that the HDAC-inhibitor SAHA activates Notch1 signaling, suppresses the neuroendocrine marker ASCL1, and inhibits growth by inducing G1 cell cycle arrest in gastrointestinal and bronchopulmonary carcinoid tumor cells. These findings suggest that SAHA represents a potential new drug for the treatment of patients with carcinoid cancer.

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