Basic research for ‘gene-regulating chemoprevention' by using food factors

丁酸酯是一种短链脂肪酸，是一类组蛋白去乙酰化酶（HDAC）抑制剂，是预防结直肠癌的重要分子。它是大肠中最丰富的短链脂肪酸之一，由细菌发酵膳食纤维产生。我们发现HDAC抑制剂丁酸酯和trichostatin A（TSA）抑制细胞增殖，并诱导p16^<INK4a>缺失的人T细胞白血病细胞株Jurkat中p18^<INK4C>和p19^<INK4d>基因的表达。此外，我们证明了HDAC抑制剂上调了死亡受体5（DR5）的表达，DR5是肿瘤坏死因子相关凋亡诱导配体（TRAIL）的受体。HDAC抑制剂对外源性可溶性重组人trail诱导的细胞凋亡具有强致敏性。吲哚-3-甲醇（I3C）是一种天然存在的化合物，存在于西兰花和花椰菜等蔬菜中，已被证明可以在细胞周期的G1期阻止人类肿瘤细胞。然而，导致这种效应的分子机制尚未得到充分阐明。我们发现I3C通过启动子激活周期蛋白依赖性激酶（CDK）抑制剂p15^<INK4b>基因，并伴随HaCaT细胞生长抑制。I3C治疗几乎不影响其他CDK抑制剂如p19^<INK4d>, p21^<WAF1>和p27^<Kip1>的表达。这些结果表明p15^<INK4b>是CDK抑制剂中I3C的重要分子靶点。p18^<INK4c>是一个单倍不足的肿瘤抑制因子。我们发现肿瘤启动子12- o - tetradecanoylphorol -13-acetate（TPA）通过其启动子抑制p18^<INK4c>的表达，同时诱导细胞生长。使用小干扰RNA减少p18^<INK4c>也能促进细胞生长，暗示p18^<INK4c>是TPA的关键靶点。蛋白激酶C抑制剂和抗肿瘤促进剂姜黄素可消除TPA对p18^<INK4c bb0的影响。而显性阴性c-Jun （TAM-67）对其无抑制作用。这些结果提示，使用TPA的小鼠两阶段癌变模型可能部分代表与RB相关的人类癌变途径。少

Butyrate, a short chain fatty acid, represents one class of histone deacetylase(HDAC) inhibitors, and is an important molecule for preventing colorectal cancer. It is one of the most abundant short chain fatty acids found in the large intestine and is generated by bacterial fermentation of dietary fibers. We discovered that the HDAC inhibitors butyrate and trichostatin A(TSA) inhibit cellular proliferation and induce the expressions of p18^<INK4C> and p19^<INK4d> genes in p16^<INK4a>-deleted human T cell leukemia cell line Jurkat. Furthermore, we demonstrated that the HDAC inhibitors up-regulate the expression of death receptor 5(DR5), a receptor for tumor necrosis factor-related apoptosis-inducing ligand(TRAIL). HDAC inhibitors strongly sensitized exogenous soluble recombinant human TRAIL-induced apoptosis.Indole-3-carbinol (I3C) is a naturally occurring compound found in vegetables such as broccoli and cauliflower, and has been shown to arrest human tumor cells in the G1 phase of the … More cell cycle. However, the molecular mechanism responsible for this effect has not been sufficiently elucidated. We found that I3C activates the cyclin-dependent kinase(CDK) inhibitor p15^<INK4b> gene through its promoter, accompanied by cell growth inhibition in HaCaT cells. Treatment with I3C almost did not affect the expressions of the other CDK inhibitors such as p19^<INK4d>, p21^<WAF1> and p27^<Kip1>. These results suggest that p15^<INK4b> is an important molecular target of I3C among CDK inhibitors.p18^<INK4c> is a haploinsufficient tumor suppressor. We showed that 12-O-tetradecanoylphorbol-13-acetate(TPA), a tumor promoter, suppresses the expression of p18^<INK4c> through its promoter, accompanied by the induction of cell growth. Reduction of p18^<INK4c> using small interfering RNA also enhanced cell growth, implicating p18^<INK4c> as a critical target of TPA. Protein kinase C inhibitor and curcumin, an anti-tumor promoting agent, abrogated the effect of TPA on p18^<INK4c>. However, dominant negative c-Jun (TAM-67) did not inhibit it. These results suggest the possibility that a mouse two-stage carcinogenesis model using TPA might partially represent human carcinogenesis pathway related to RB. Less