Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention.
Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention.
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DOI：
10.1158/1078-0432.ccr-13-2483
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发表时间：
2014-02-15
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影响因子：
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通讯作者：
Bultman SJ
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作者：
Bultman SJ
基因与环境的相互作用如此之多且生物学上如此复杂，以至于了解它们在癌症中的作用可能具有挑战性。然而，膳食纤维和结直肠癌预防可能代表一个易于处理的模型系统。纤维被结肠细菌发酵成短链脂肪酸，例如丁酸盐。已出现的一种分子途径涉及丁酸，其作用取决于其浓度和细胞的代谢状态。存在于结肠隐窝底部附近的中低浓度很容易在线粒体中代谢，通过能量刺激细胞增殖。管腔附近存在的较高浓度超过了结肠细胞的代谢能力。未代谢的丁酸盐进入细胞核，并作为组蛋白脱乙酰酶 (HDAC) 抑制剂发挥作用，在结肠细胞脱落到腔内时，通过表观遗传调节基因表达来抑制细胞增殖并诱导细胞凋亡。因此，丁酸盐可能通过促进结肠上皮的更新而在正常体内平衡中发挥作用。由于癌性结肠细胞会经历瓦尔堡效应，因此它们的首选能量来源是葡萄糖而不是丁酸盐。因此，即使是中等浓度的丁酸盐也会在癌性结肠细胞中积聚，并作为 HDAC 抑制剂抑制细胞增殖并诱导细胞凋亡。这些发现表明具有代谢表观遗传特性的细菌代谢物可抑制肿瘤。
Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression.