Li Ran, Gan Ye-Hua
Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
Int J Mol Sci. 2017 May 8;18(5):1010. doi: 10.3390/ijms18051010.
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.
羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，即他汀类药物，是潜在的抗肿瘤药物。此前，我们发现一种泛组蛋白去乙酰化酶（HDAC）抑制剂可增强HMG-CoA抑制剂的抗肿瘤作用。然而，其潜在机制尚未完全明确。将癌细胞系（CAL-27和SACC-83）单独或与他汀类药物联合暴露于泛HDAC抑制剂、HDAC1抑制剂或I型香叶基香叶基转移酶（GGTase-I）抑制剂。分别通过细胞计数试剂盒-8、4',6-二脒基-2-苯基吲哚染色和Transwell实验评估细胞活力、凋亡、迁移和侵袭情况。采用异种移植模型评估体内肿瘤生长情况。通过蛋白质免疫印迹法和实时荧光定量PCR评估基因表达。我们观察到，抑制HDAC1在体外和体内均可增强他汀类药物的抗肿瘤作用。抑制HDAC1可阻断他汀类药物诱导的I型香叶基香叶基转移酶β亚基（GGTase-Iβ）上调，从而增强他汀类药物的抗癌作用。GGTase-Iβ的过表达或组成型活性RhoA消除了抑制HDAC1对他汀类药物抗肿瘤作用的增强效果。HDAC1抑制剂未能增强用他汀类药物处理的非肿瘤原代细胞的细胞毒性。抑制HDAC1通过下调GGTase-Iβ表达，进而使RhoA进一步失活，增强了他汀类药物的抗癌作用。他汀类药物与HDAC1或GGTase-I抑制剂联合使用将成为癌症化疗的新策略。
