桿狀病毒表現系統是目前相當成功的真核生物表現系統之一，其廣泛被利用在基礎病毒學研究、外源蛋白的生產、基因治療、生物殺蟲劑等。本研究則嘗試研發重組桿狀病毒作為藥物篩選之平台。篩藥原理為：假如一個藥物是 Histone deacetylase inhibitor (HDACi)，那麼該藥物可透過穩定胞內組蛋白乙醯化的狀態，進而增加桿狀病毒所攜帶之外源基因 (如綠螢光基因) 的表現效率。利用此篩藥平台篩選 699 個候選藥物，其中綠螢光強度和對照組比較後，增加 3 倍以上的藥物有 45 個，增加 4 倍以上的藥物有14個。其中 Malotilate (MT)、Vorinostat (SAHA) 及 Sodium salicylate 可透過增加胞內組蛋白乙醯化而增加桿狀病毒表達外源基因的效率。然而，已有文獻指出 SAHA 及 Sodium salicylate 為 HDACi，但尚未有文獻指出 MT 具有抑制 HDACs 酵素活性之功能。篩選藥物的過程中發現拓撲異構酶抑制劑：Teniposide (VM-26)、Etoposide (VP-16) 可以明顯地增加綠螢光蛋白的表現量，但卻是透過誘發胞內 DNA damage response (DDR) 而造成。利用篩選到的藥物 (MT 及 VM-26) 配合抑癌蛋白 p53 的策略可以成功地殺死骨肉瘤細胞 (U2OS)，效果類似 NaBt 配合 p53。透過 RNAi 干擾技術分析標準型 HDACs (HDAC1~11) 後發現桿狀病毒轉導哺乳動物細胞時，HDAC4 對於外源基因的表現扮演重要的角色。總合上述之結果：一、重組桿狀病毒可以有效地用來作為 HDACi 的初步篩選平台。二、除了穩定胞內組蛋白乙醯化的狀態外，誘發胞內 DDR 也可以增加桿狀病毒轉導 U2OS 細胞後表現外源基因之效率。三、HDAC 參與抑制桿狀病毒表達外源基因之效率，其中又以 HDAC4 較為重要。

Baculovirus expression system (BEVS) is one of the successful eukaryotic expression system and used widely in basic virological researches, exogenous protein productions for medical usages and structure studies, gene therapy and development of biological insecticides. In this study, we developed recombinant baculovirus as a drug screening platform by the screening rational: if the compound(s) is/are HDACis then it(they) will enhance the baculovirus-mediated gene expression in mammalian cells and also stabilize the hyperacetylation state of histone. Through this drug screeing platform, we screened 699 candidates. Comparing to the control group, there are 45 drugs whose green fluorescence intensities are three times and 14 candidates whose green fluorescence intensities are fourth times. Three candidates, I-E6 (Malotilate, MT), III-H8 (Vorinostat, SAHA) and V-G1 (Sodium salicylate), can increase the level of acetyl histone H4 in U2OS cells. SAHA and Sodium salicylate have been reported as HDACis; however, no references indicated that MT is a HDACi. On the other hand, we found that topoisomerase inhibitors: Teniposide (VM-26), Etoposide (VP-16) can significantly increase the baculovirus-mediated green fluorescent protein expression by inducing intracellular DNA damage response (DDR). Combining MT and VM-26 with the tumor suppressor protein, p53 successfully killed osteosarcoma cells (U2OS), a similar effect combining NaBt with p53. Using RNA interference (RNAi) to analyze standard HDACs (HDAC1-11) and identifing HDAC4 as the critical factor for baculovirus transduction. These findings suggest recombinant baculovirus has a new application to be a screening platform for HDACis. In addition to stabilizing intracellular histone acetylation state, DDR can also increase the efficiency of exogenous gene exprssion in baculovirus- transduced U2OS cells. HDACs involved in the inhibition of baculovirus-mediated gene expression and HDAC4 is the more critical factor.

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