Statins inhibit tumor progression via an enhancer of zeste homolog 2‐mediated epigenetic alteration in colorectal cancer

While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin‐induced antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin ≥ fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin‐mediated antiproliferative effects depended on non‐mevalonate pathway. Indeed, statin induced p27KIP1 expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27KIP1 by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27KIP1 expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2‐mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC. What's new? Although statin use is associated with reduced colorectal cancer risk, the mechanism by which the drugs exert antitumor effects and their benefits for survival remain unclear. Here, experimental and clinical statin‐associated anticancer effects were found to differ for different kinds of statins. For example, while both simvastatin and pravastatin activated the mevalonate pathway in colon cancer cells, of the two drugs, only simvastatin displayed non‐mevalonate‐pathway antiproliferative effects via induction of p27KIP1 and epigenetic silencing by enhancer of zeste homolog 2 (EZH2). Statin‐induced downregulation of EZH2 and upregulation of p27KIP1 was associated with improved overall and disease‐free survival.