Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells

Abstract

Statins, also known as HMG-CoA reductase inhibitors, are a class of cholesterol-lowering drugs and their anti-cancer effects have been studied in different types of malignant diseases. In the present study, we investigated the anti-proliferative effects of statins, including cerivastatin and simvastatin, on oral squamous cell carcinoma (OSCC) cells. Our data showed that statins inhibited the proliferation of three OSCC cell lines in a dose-dependent manner and this growth inhibition was confirmed through G0/G1 cell cycle arrest. Accordingly, we found the upregulation of p21 and downregulation of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, in the statin-treated cells. Importantly, we clearly showed that statins were able to inhibit the expression of DNA methyltransferase 1 (DNMT1) and further promote the expression of p21. Taken together, our data demonstrated that the anti-proliferative effect of statins is mediated by suppressing DNMT1 expression, thus promoting p21 expression and leading to G0/G1 cell cycle arrest in OSCC cells.

Determination of Major Endogenous FAHFAs in Healthy Human Circulation: The Correlations with Several Circulating Cardiovascular-Related Biomarkers and Anti-Inflammatory Effects on RAW 264.7 Cells

“…The PCR reaction with 40 cycles (10 min hold at 95 °C, 15 s denature at 95 °C, annealing, and extension 1 m at 60 °C) of amplification was performed using instrument QuantStudio ® 5 System (Thermo Fisher, USA) and analyzed using comparative CT (△△CT). Each RT-qPCR was repeated with at least four to five different RNA and cDNA preparations for both control and treated cells [ 27 ].…”

Heparanase: A Novel Therapeutic Target for the Treatment of Atherosclerosis

“…Importantly, in clinical practice, particularly in secondary prevention of atherosclerosis, statins are recommended in all acute myocardial infarction patients without contraindications to statin use, regardless of lipid profile, in order to lower the risk of mortality based on the recommendations of current guidelines [ 59 , 60 , 61 , 62 ]. This is due to the pleiotropic effect of statins including stabilisation of the atherosclerotic plaques, anti-inflammatory, antioxidative, and antiproliferative effects [ 63 , 64 ]. However, despite the widespread use of statins for the prevention of atherosclerosis, several challenges remain.…”

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

“…Statin was studied in vitro for its anti-proliferative and apoptotic effect in cancer cells such as medulloblastoma brain tumor, colorectal cancer, lung cancer, oral squamous cell carcinoma, anaplastic thyroid cancer, and hepatic cancer ( Figure 2 ) [ 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Lovastatin augments sensitivity by activating bone morphogenetic protein (BMP), a tumor-suppressive protein, and reducing cancer stemness in colorectal cancer cells [ 61 ].…”

“…Lovastatin augments sensitivity by activating bone morphogenetic protein (BMP), a tumor-suppressive protein, and reducing cancer stemness in colorectal cancer cells [ 61 ]. The anti-cancer effect of statin is also mediated by inhibiting the activity of DNA methyltransferases (DNMTs) [ 60 , 61 ], leading to demethylation and activation of BMP signaling, which causes a shift in the stem-like state to a differentiated form of cancer cells [ 61 ] and induction of p21 cip , causing cell-cycle arrest [ 60 ]. In contrast, it inhibits breast cancer cell proliferation via induction of cell-cycle arrest and apoptosis [ 62 , 63 ].…”