J Cancer 2015; 6(10):996-1004. doi:10.7150/jca.12135

Research Paper

The Histone Deacetylase Inhibitor Vaproic Acid Induces Cell Growth Arrest in Hepatocellular Carcinoma Cells via Suppressing Notch Signaling

Guangchun Sun1, Lily V. Mackey3, David H. Coy3, Cui-Yun Yu2,3,✉, Lichun Sun1,2,3,✉

1. Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University; 801 He-Qing Rd., Shanghai 200240, China
2. Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
3. Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA

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Sun G, Mackey LV, Coy DH, Yu CY, Sun L. The Histone Deacetylase Inhibitor Vaproic Acid Induces Cell Growth Arrest in Hepatocellular Carcinoma Cells via Suppressing Notch Signaling. J Cancer 2015; 6(10):996-1004. doi:10.7150/jca.12135. Available from http://www.jcancer.org/v06p0996.htm

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Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents.

Keywords: valproic acid, HDAC inhibitor, Notch signaling, hepatocellular carcinoma, receptor-targeting.