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Abstract
The therapeutic effects of simvastatin for renal cell carcinoma (RCC) are controversial. In this study, the effects of simvastatin on the carcinogenic properties of 3-methylcholanthrene (3MC; an aryl-hydrocarbon receptor [AhR] agonist) in human renal epithelial cells (hRECs) were investigated. We exposed in vitro and in vivo models to 3MC to induce RCC onset. 3MC upregulated the epithelial–mesenchymal transition (EMT) and tumor biomarkers; the models exhibited the reciprocal expression of histone deacetylase 1 (HDAC1) and RhoA, namely increased HDAC1 and decreased RhoA expression, through hypoxia-inducible-factor (HIF)- and AhR-dependent mechanisms. In addition to inducing EMT biomarkers, 3MC decreased von Hippel–Lindau protein levels (a risk factor for RCC) and increased CD44 expression in hRECs, which were reversed by digoxin (a HIF inhibitor) and HDAC inhibitors (suberoylanilide hydroxamic acid and trichostatin A [TSA]). Simvastatin abolished the detrimental effects of 3MC by reducing HDAC1 expression, with resulting RhoA upregulation, and reactivating RhoA in vitro and in vivo. Notably, the protective effects of simvastatin were negated by an HDAC activator (ITSA) through TSA suppression. The crucial role of RhoA in RCC carcinogenesis was verified by the overexpression of constitutively active RhoA. Collectively, these results demonstrate that simvastatin restores RhoA function through HDAC1 inhibition; therefore, simvastatin might serve as adjunct therapy for RCC induced by 3MC.
Highlights
The therapeutic effects of simvastatin for renal cell carcinoma (RCC) are controversial
Molecular modeling suggests that statins in acid form, which possess a carboxylic-acid-containing long chain, exhibit similar structures to those of trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), and that they chelate the catalytic site of human histone deacetylase 2 (HDAC2)[14]
We revealed that 3MC reduced pVHL levels and activated the hypoxia signaling pathway by increasing HIF1α levels. 3MC upregulated histone deacetylase 1 (HDAC1), inhibited RhoA expression through a hypoxia-inducible factors (HIFs)-aryl-hydrocarbon receptor (AhR)-HDAC1-dependent mechanism, and reduced expression of p190RhoGEF, a RhoA activator
Summary
The therapeutic effects of simvastatin for renal cell carcinoma (RCC) are controversial. These results demonstrate that simvastatin restores RhoA function through HDAC1 inhibition; simvastatin might serve as adjunct therapy for RCC induced by 3MC. Molecular modeling suggests that statins in acid form, which possess a carboxylic-acid-containing long chain, exhibit similar structures to those of trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), and that they chelate the catalytic site of human histone deacetylase 2 (HDAC2)[14] These properties enable statins to inhibit HDAC activity and increase the hyperacetylation of histone H3 in human lung cancer cells[14]. A recent systematic review and meta-analysis demonstrated that statin administration is associated with significantly improved cancer-specific and overall survival among patients with kidney cancer[20]
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