Contribution of reactivated RUNX3 to inhibition of gastric cancer cell growth following suberoylanilide hydroxamic acid (vorinostat) treatment
Contribution of reactivated RUNX3 to inhibition of gastric cancer cell growth following suberoylanilide hydroxamic acid (vorinostat) treatment
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DOI：
10.1016/j.bcp.2006.12.013
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发表时间：
2007-04-01
影响因子：
5.8
通讯作者：
Ito, Yoshiaki
中科院分区：
文献类型：
--
作者：
Huang, Canhua;Ida, Hiroshi;Ito, Yoshiaki
伏立诺司特(Suberoylanilide IOHa，SAHA)是一类新型高效的组蛋白脱乙酰酶(HDAC)抑制剂，可在体内外引起多种肿瘤类型的生长停滞、分化和凋亡。RUNX3是一种胃肿瘤抑制因子，在胃癌细胞中是表观遗传沉默的。本研究探讨RUNX3在伏立诺抑制胃癌细胞生长中的作用。在不表达RUNX3的胃癌细胞系中，伏立宁上调了RUNX3的表达。在细胞活力方面，RUNX3阴性细胞的平均IC50显著低于RUNX3阳性细胞，表明前者比RUNX3阳性细胞更敏感。这种差异的机制被发现是由于涡旋调节剂重新激活了RUNX3的表达，并伴随着RUNX3启动子区域乙酰化组蛋白H3的增加。使用三个RUNX3阴性的细胞系，我们确定了RUNX3的重新激活在用涡旋加速器处理细胞后对生长抑制和诱导凋亡的贡献，发现上调的RUNX3对肿瘤抑制活性有显著的作用。(C)2007 Elsevier Inc.保留所有权利。
Vorinostat (suberoylanilide hydroxamic acid, SAHA) represents a new class of highly potent histone deacetylase (HDAC) inhibitors that cause growth arrest, differentiation, and apoptosis of many tumor types in vitro and in vivo. RUNX3, a gastric tumor suppressor, is epigenetically silenced in gastric cancer cells. This study investigates the role of RUNX3 in vorinostat-induced suppression of gastric cancer cell growth. RUNX3 was up-regulated by vorinostat in gastric cancer cell lines not expressing RUNX3. In terms of cell viability, the mean IC50 of vorinostat in RUNX3-negative cells was significantly lower than that seen in RUNX3-positive cells, indicating that the former are more sensitive to vorinostat in terms of growth arrest than are RUNX3-positive lines. The mechanism underlying this difference was found to be reactivation of RUNX3 expression by vorinostat and concomitant increase in acetylated histone H3 in the promoter region of RUNX3. Using three RUNX3-negative cell lines, we determined the contribution of RUNX3 reactivation to growth inhibition and induction of apoptosis following treatment of cells with vorinostat and found that up-regulated RUNX3 was significantly responsible for tumor suppressive activities. (c) 2007 Elsevier Inc. All rights reserved.