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Statins inhibit tumor progression via an enhancer of zeste homolog 2‐mediated epigenetic alteration in colorectal cancer
Author(s) -
Ishikawa S.,
Hayashi H.,
Kinoshita K.,
Abe M.,
Kuroki H.,
Tokunaga R.,
Tomiyasu S.,
Tanaka H.,
Sugita H.,
Arita T.,
Yagi Y.,
Watanabe M.,
Hirota M.,
Baba H.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28672
Subject(s) - statin , ezh2 , cancer research , simvastatin , pravastatin , histone deacetylase inhibitor , histone deacetylase , colorectal cancer , epigenetics , vorinostat , medicine , downregulation and upregulation , mevalonate pathway , lovastatin , cancer , biology , pharmacology , histone , cholesterol , reductase , biochemistry , gene , enzyme
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 p27 KIP1 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 p27 KIP1 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 p27 KIP1 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.