Yochum Gregory S, McWeeney Shannon, Rajaraman Veena, Cleland Ryan, Peters Sandra, Goodman Richard H
Department of Public Health and Preventative Medicine, and Oregon Health & Science University Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3324-9. doi: 10.1073/pnas.0611576104. Epub 2007 Feb 21.
Most instances of colorectal cancer are due to abnormalities in the Wnt signaling pathway, resulting in nuclear accumulation of beta-catenin. beta-Catenin activates transcription of target genes primarily by associating with the T cell factor/lymphoid enhancer-binding factor (TCF/Lef) family of transcription factors. In this report, we use serial analysis of chromatin occupancy (SACO) to identify 412 high-confidence beta-catenin targets in HCT116 colorectal carcinoma cells. Of these targets, 84% contained a consensus TCF motif and were occupied by TCF4 in vivo. Examination of the flanking 5-bp residues in each consensus revealed motif-specific enrichment at neighboring sites. beta-Catenin binding was localized to the 5' promoters, internal regions, and 3' UTRs of protein-coding genes. Furthermore, 15 components of the canonical Wnt pathway were identified as beta-catenin target genes, suggesting that feed-forward and feedback mechanisms exist to modulate the Wnt signal in colon cancer cells.
大多数结直肠癌病例是由于Wnt信号通路异常，导致β-连环蛋白在细胞核内积累。β-连环蛋白主要通过与转录因子T细胞因子/淋巴增强子结合因子（TCF/Lef）家族结合来激活靶基因的转录。在本报告中，我们使用染色质占据序列分析（SACO）来鉴定HCT116结肠癌细胞中412个高可信度的β-连环蛋白靶标。在这些靶标中，84%含有共有TCF基序，并且在体内被TCF4占据。对每个共有序列侧翼5个碱基残基的检查显示相邻位点存在基序特异性富集。β-连环蛋白结合定位于蛋白质编码基因的5'启动子、内部区域和3'UTR。此外，经典Wnt通路的15个成分被鉴定为β-连环蛋白靶基因，这表明存在前馈和反馈机制来调节结肠癌细胞中的Wnt信号。
