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Int. J. Mol. Sci. 2017, 18(5), 1010; doi:10.3390/ijms18051010

Inhibiting HDAC1 Enhances the Anti-Cancer Effects of Statins through Downregulation of GGTase-Iβ Expression

1,2
and
1,2,*
1
Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, China
2
Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Academic Editor: Charles Brennan
Received: 26 March 2017 / Revised: 23 April 2017 / Accepted: 1 May 2017 / Published: 8 May 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [9309 KB, uploaded 8 May 2017]   |  

Abstract

Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, namely statins, are potential anti-tumor agents. Previously, we showed that a pan-histone deacetylase (HDAC) inhibitor enhances the anti-tumor effects of the HMG-CoA inhibitor. However, the underlying mechanisms were not fully understood. Cancer cell lines (CAL-27 and SACC-83) were exposed to pan-HDAC inhibitor, or HDAC1 inhibitor, or geranylgeranyl transferase type I (GGTase-I) inhibitor alone or in combination with statin. Cell viability, apoptosis, migration, and invasion were assessed by Cell Count Kit-8, 4′,6-diamidino-2-phenylindole staining, and transwell assay, respectively. A xenograft model was used for assessing tumor growth in vivo. Western blot and real-time PCR were used to assess the expression of genes. We observed that inhibiting HDAC1 could enhance the anti-tumor effects of statins both in vitro and in vivo. Inhibiting HDAC1 blocked the statin-induced upregulation of geranylgeranyl transferase type Iβ subunit (GGTase-Iβ), resulting in an enhancement of the anti-cancer effects of statin. Overexpression of GGTase-Iβ or constitutively active RhoA abolished the enhancement by inhibiting HDAC1 on anti-tumor effects of statins. The HDAC1 inhibitor failed to enhance cytotoxicity in non-tumor primary cells treated with statin. Inhibiting HDAC1 enhanced the anti-cancer effects of statins through downregulation of GGTase-Iβ expression, and thus further inactivation of RhoA. A combination of statin with HDAC1 or GGTase-I inhibitor would be a new strategy for cancer chemotherapy. View Full-Text
Keywords: head and neck cancers; statin; HDAC1; GGTase-Iβ; RhoA; chemotherapy head and neck cancers; statin; HDAC1; GGTase-Iβ; RhoA; chemotherapy
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Li, R.; Gan, Y.-H. Inhibiting HDAC1 Enhances the Anti-Cancer Effects of Statins through Downregulation of GGTase-Iβ Expression. Int. J. Mol. Sci. 2017, 18, 1010.

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