CDX Transcription Factors Positively Regulate Expression of Solute Carrier Family 5, Member 8 in the Colonic Epithelium
CDX Transcription Factors Positively Regulate Expression of Solute Carrier Family 5, Member 8 in the Colonic Epithelium
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DOI：
10.1053/j.gastro.2009.10.047
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发表时间：
2010-02-01
期刊：
影响因子：
29.4
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
--
作者：
Kakizaki, Fumihiko;Aoki, Koji;Taketo, Makoto M.
背景与目的：尾部相关的同源域转录因子CDX 1和CDX 2调节肠道发育和肠上皮细胞的分化，它们是结直肠癌的候选肿瘤抑制因子。由于CDX 1和CDX 2在结肠上皮中的功能尚未完全了解，我们试图确定它们靶向的基因。方法：我们进行了染色质免疫沉淀（ChIP）筛选，以确定结合CDX转录因子的基因。在Cdx 1（-/-）、Cdx 2（+/-）、Apc（+/Delta 716）和野生型（对照）小鼠的结肠细胞和组织中分析靶基因的表达。结果：使用ChIP筛选，我们鉴定了溶质载体家族5，成员8（SLC 5A 8，也称为SMCT 1）作为CDX 1和CDX 2的直接靶点。CDX转录因子与SLC 5A 8的启动子区结合并反式激活SLC 5A 8报告构建体。Cdx 1或Cdx 2在人结肠癌细胞系中的过表达诱导内源性SLC 5A 8的表达，而CDX 1和CDX 2敲除降低了其水平。与野生型小鼠相比，Cdx 1（-/-）或Cdx 2（+/-）小鼠结肠中Slc 5a 8表达显著降低。与邻近的正常结肠组织相比，分别来自Apc（+/Delta 716）和Cdx 2（+/-）突变小鼠的结肠腺瘤性息肉和错构瘤中的Slc 5a 8水平也降低。结论：CDX 1和CDX 2与SLC 5A 8的启动子区结合，上调其在培养细胞和结肠上皮中的表达。SLC 5A 8转运单羧酸盐，如丙酮酸盐、乳酸盐和丁酸盐;因此，CDX 1和CDX 2可能调节这些物质在结肠中的摄取。
BACKGROUND & AIMS: Caudal-related homeodomain transcription factors CDX1 and CDX2 regulate gut development and differentiation of intestinal epithelial cells; they are candidate tumor suppressors of colorectal carcinomas. Because the functions of CDX1 and CDX2 in the colonic epithelium are not fully understood, we sought to identify genes that they target. METHODS: We conducted a chromatin immunoprecipitation (ChIP) screen to identify genes that bind the CDX transcription factors. Expression of target genes was analyzed in colon cells and tissues from Cdx1(-/-), Cdx2(+/-), Apc(+/Delta 716), and wild-type (control) mice. RESULTS: Using the ChIP screen, we identified solute carrier family 5, member 8 (SLC5A8, also known as SMCT1) as a direct target of CDX1 and CDX2. CDX transcription factors bind to the promoter region of SLC5A8 and transactivate SLC5A8 reporter constructs. Overexpression of Cdx1 or Cdx2 in human colon cancer cell lines induced expression of endogenous SLC5A8, whereas CDX1 and CDX2 knockdowns reduced its level. Consistently, Slc5a8 expression was significantly reduced in colons of Cdx1(-/-) or Cdx2(+/-) mice compared with wild-type mice. Slc5a8 levels were also reduced in colonic adenomatous polyps and hamartomas from Apc(+/Delta 716) and Cdx2(+/-) mutant mice, respectively, compared with adjacent normal colon tissues. CONCLUSIONS: CDX1 and CDX2 bind the promoter region of SLC5A8 and up-regulate its expression in cultured cells and in colonic epithelium. SLC5A8 transports monocarboxylates such as pyruvate, lactate, and butyrate; CDX1 and CDX2 might therefore regulate the uptake of these substances in the colon.