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

Abstract

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.

Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2

“…However, some other reports showed suppressive effects of Notch signaling in HCC cells [9, 12]. The controversy lead us to confirm the role of Notch signaling in HCCs.…”

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

“…FD-conditioned HCC cells contained a lower level of miR-22 leading to the elevated level of HDAC4, an established oncogenic epigenetic modifier [40, 41], may provide a partial and mechanistic explanation for the association between cancer development and folate deficiency. Added support from a recent study indicated that vaproic acid, a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth [42]. …”

Expression and influence of Notch signaling in oral squamous cell carcinoma

“…The siRNA targeting HDAC1 in OSCC cell line led to a decrease in cell proliferation and an increase in cell apoptosis (48). It has been shown that HDAC inhibitor could inhibit hepatocellular carcinoma cell proliferation by attenuating NOTCH1 and HES1 expression (49). However, the role of HDAC in Notch signaling in OSCC remains unclear.…”