Anticancer effects of valproic acid on oral squamous cell carcinoma via SUMOylation in vivo and in vitro

Abstract

Aberrant histone deacetylase (HDAC) has a key role in the neoplastic process associated with the epigenetic patterns of tumor-related genes. The present study was performed to investigate the effects and determine the mechanism of action of the HDAC inhibitor, valproic acid (VPA), on the CAL27 cell line derived from oral squamous cell carcinoma (OSCC). The effects of VPA on the viability of CAL27 cells were investigated using MTT assays. Alterations in the cell cycle and apoptosis were also examined using propidium iodide (PI) and Annexin V-PI assays, and were subequently analyzed by flow cytometry. Small ubiquitin-related modifier (SUMO)-related genes were evaluated by reverse transcription-quantitative polymerase chain reaction analysis. In addition, the effects of VPA were assessed using a xenograft model in vivo. The present results demonstrated significant dose-dependent inhibition of cell viability following VPA treatment. Treatment with VPA increased the distribution of CAL27 cells in the G1 phase and reduced cells in the S phase, and significantly increased the expression levels of SUMO1 and SUMO2 (P<0.01). Using a xenograft model, the mean tumor volume in VPA-treated animals was demonstrated to be significantly reduced, and the rate of apoptosis was significantly increased, as compared with the control animals. These results suggested that VPA may regulate SUMOylation, producing an anticancer effect in vivo. Further investigation into the role of VPA in tumorigenesis may identify novel therapeutic targets for OSCC.

GANT61 and Valproic Acid Synergistically Inhibited Multiple Myeloma Cell Proliferation via Hedgehog Signaling Pathway

“…VPA has emerged as one of the most promising anti-cancer agents for human cancers [28]. It functions as the HDACi mediating the cell differentiation, apoptosis, and cell cycle arrest [29].…”

DynOVis: a web tool to study dynamic perturbations for capturing dose-over-time effects in biological networks

“…These different dynamic gene-gene interactions are of interest because they may play a role in the same biological processes that lead to the adverse outcome of VPA exposure [32]. PCNA is a nuclear protein involved in DNA-synthesis and repair and decreased expression of PCNA has been experimentally shown in tumours of VPA treated mice [33]. ITIH2 belongs to the family of plasma serine protease inhibitors involved in stabilization and prevention of tumour metastasis.…”

HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder cancer cells

“…The effect of VPA on bladder cancer progression was associated with an accumulation in the G0/G1-phase and concomitant decrease of S-phase cells. Reports point to a G0/G1-phase arrest, paralleled by a reduction of S-phase cells, as the main mechanism of VPA on several tumor entities such as oral squamous cell carcinoma [ 45 ], ovarian cancer [ 46 ], endometrial cancer [ 47 ], renal cell [ 15 ] and prostate carcinoma cells [ 48 ]. Interestingly, G2/M phase cells were also diminished in both UMUC-3 par and UMUC-3 res cultures, whereas VPA lowered the number of RT112 res but not of RT112 par G2/M phase cells.…”