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.
Highlights
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, namely statins, are clinically used for lowering cholesterol by inhibiting the mevalonate pathway, with a relatively low price and good safety [1,2]
Our results showed that inhibition of GGTase-Iβ expression by inhibiting HDAC1 was not due to the influence on its promoter activity, but to the destabilization of its mRNA by some proteins regulated by HDAC1, for which detailed mechanisms need to be further explored
Stable transfection of constitutively active RhoA (CA-RhoA), rescued mevastatin-induced inhibition of cell viability, and abolished the enhancement by inhibiting HDAC1 of mevastatin-induced cell proliferation inhibition and apoptosis. These results strongly suggested that RhoA was the key target among the 22 members of the Rho family for cell survival and proliferation, underlying the statin treatment and the combinational treatment of statin and HDAC1 inhibitor
Summary
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, namely statins, are clinically used for lowering cholesterol by inhibiting the mevalonate pathway, with a relatively low price and good safety [1,2]. IInnhhiibbiittiioonn ooff GGGGTTaassee--IIββ aallssoo EEnnhhaanncceedd tthhee AAnnttii--CCaanncceerr EEffffeeccttss ooff SSttaattiinn IInn pprreevviioouuss ssttuuddyy,, wwee ssppeeccuullaatteedd tthhaatt ddoowwnnrreegguullaattiioonn ooff GGGGTTaassee--IIββ bbyy ppaann--HHDDAACC iinnhhiibbiittoorr. TToo ccoonnfifirrmm tthhiiss ssppeeccuullaattiioonn,, wwee fifirrsstt eexxaammiinneedd wwhheetthheerr tthhee iinnhhiibbiittiioonn ooff GGGGTTaassee--II ccoouulldd ggeenneerraattee ssiimmiillaarr eeffffeeccttss ttoo SSAAHHAA oonn tthhee aannttii--ccaanncceerr eeffffeeccttss ooff ssttaattiinnss iinn CCAALL2277 aanndd SSAACCCC--8833 cceellllss. GGGGTTaassee--IIββ MMeeddiiaatteedd tthhee SSyynneerrggiissttiicc AAnnttii--CCaanncceerr EEffffeeccttss ooff HHDDAACC11 IInnhhiibbiittoorr aanndd SSttaattiinn WWee nneexxtt eexxaammiinneedd wwhheetthheerr GGGGTTaassee--IIββ mmeeddiiaatteedd tthhee eennhhaanncceemmeenntt bbyy ppaann--HHDDAACC iinnhhiibbiittoorr oorr. The inhibition of HDAC1 was responsible for the pan-HDAC inhibitor-induced enhancement of statin anti-cancer effects. We showed that the inhibition of HDAC1 was responsible for pan-HDAC inhibitors enhancing the anti-cancer effects of statins; the inhibition of HDAC1 enhanced statin-induced inhibition of proliferation through a downregulation of GGTase-Iβ expression in cancer cells, but not in non-cancer primary cells. Our results suggested that the combination of HDAC1 inhibitor and a statin would be a potential new regimen for cancer therapeutics
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