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

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.

Network Analysis Reveals the Molecular Bases of Statin Pleiotropy That Vary with Genetic Background

“…For the Y55 background, it was the deletion of BTS1 with RPD3 that increased the chronological life span. RPD3 is a histone deacetylase gene orthologue to the human HDAC1 and HDAC2 genes, which have been linked to the mechanism of anticancer activity of statins ( 76 , 77 ), and HDAC1 is known to have an antiaging activity in brain cells ( 78 ). We note that statins increase the life span of the model organism Caenorhabditis elegans ( 79 ) and decreased mortality independent of cholesterol in humans 78 to 90 years old ( 47 ).…”

Network analysis reveals the molecular bases of statin pleiotropy that vary with genetic background

“…For the Y55 background, it was the deletion of BTS1 with RPD3 that increased the chronological lifespan. RPD3 is a histone deacetylase orthologue to the human HDAC1 and HDAC2, which have been linked to the mechanism of anticancer activity of statins (Li & Gan 2017; Lin et al 2008), and HDAC1 is known to have an anti-ageing activity in brain cells (Pao et al, 2020). We note that statins increase the lifespan of the model organism Caenorhabditis elegans (Jahn et al 2020) and decreased mortality independent of cholesterol in humans aged 78-90 years old (Jacobs et al 2013).…”

An Aptamer-Based Antagonist against the Receptor for Advanced Glycation End-Products (RAGE) Blocks Development of Colorectal Cancer

“…The CCK8 assay was carried out to determine relative cell viability. [ 21 ] HCT116 cells were seeded at 5 × 10 3 cells/well on a 96-well plate culture dish (Wuxi NEST Biotechnology Co., Ltd.) and allowed to adhere for 24 h at 37°C in 5% CO 2 . The cells were pretreated with Apt-RAGE (100 nM) and then treated with S100B (2 ugs/mL), S100B within the fresh medium for 24 h, 48 h, or 72 h. After the incubation, cells within the 96-well plate were incubated with CCK8 solution for 1-3 h at 37°C in 5% CO 2 , followed by measurement using a GENios Microplate Reader (TECAN) at the absorbance at 450 nm.…”

“…The CCK8 assay was carried out to determine relative cell viability. [21] HCT116 cells were seeded at 5 × 10 3 cells/well on a 96-well plate culture dish (Wuxi NEST Biotechnology Co., Ltd.) and allowed to adhere for 24 h at 37°C in 5% CO 2 . The cells were pretreated with 2…”