Molecular mechanism of involvement of homeobox transcription factors Cdx2 and Cdxl in intestinal tumors

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The caudal-type homeobox transcription factors Cdx2 and Cdx1 ate involved in differentiation and tumorigenesis of intestinal epthelial cells, yet the underlying molecular mechanisms remain unclear. In this study, we have identified SLC5A8 and PLEKHG1 as novel target genes of Cdx2 and Cdx1, by using an improved version of chromatin immunoprecipitation (ChIP) screen. SLC5A8 codes for a sodium-coupled transporter for short chain fatty adds and monocarboxylates, including butyrate and pyruvate. Expression of SLC5A8 is frequently down regulated in colon cancer, and higher expression of SLC5A8 correlates with longer disease-free survival in colon cancer patients. Reporter gene assays using SLC5A8 promoter and qRT-PCR analysis of SLC5A8 in human colon cancer cell fines following forced expression or knockdown of CDX2 and/or CDX1 have shown that SLC5A8 is indeed a direct transcriptional target of Cdx2 and Cdx1. On the other hand, PLEKHG1 encodes a protein with 1385 amino acids, carrying Dbl-homology (DH) domain and pleckstrin homology (PH) domain. Although ft is expected to function as a GTP/GDP exchange factor (GEF) for Rho/Rac/Cdc42 family small G-proteins, no reports have been published of this molecule. We have found that PLEKHG1 is expressed in the normal intestinal tissues as well as in a subset of colon cancer cell lines, and that its expression is regulated by CDX2 and CDX1. Further characterization of these novel target genes of Cdx is expected to reveal their roles in differentiation and/or tumorigenesis of the intestinal epithelial cells. We have also shown that PKC ζ, an atypical PKC involved in cell polarity control, can phosphorylate a well-conserved threonine reside in the homeodomain of Cdx2, and that phosphorylation of this residue may regulate dimerization of Cdx2. Further analysis of the possible link between PKC signaling and Cdx2 may he understand the mechanism by which Cdx2 controls their differentiation and transformation.