CDX2 Regulates Multidrug Resistance 1 Gene Expression in Malignant Intestinal Epithelium

Abstract

The caudal-related homeobox transcription factor CDX2 has a key role in intestinal development and differentiation. CDX2 heterozygous mutant mice develop colonic polyps, and loss of CDX2 expression is seen in a subset of colon carcinoma in man. Ectopic CDX2 expression in the stomach of transgenic mice promotes intestinal metaplasia, and CDX2 expression is frequently detected in intestinal metaplasia in the stomach and esophagus. We sought to define CDX2-regulated genes to enhance knowledge of CDX2 function. HT-29 colorectal cancer cells have minimal endogenous CDX2 expression, and HT-29 cells with ectopic CDX2 expression were generated. Microarray-based gene expression studies revealed that the Multidrug Resistance 1 (MDR1/P-glycoprotein/ABCB1) gene was activated by CDX2. Evidence that the MDR1 gene was a direct transcriptional target of CDX2 was obtained, including analyses with MDR1 reporter gene constructs and chromatin-immunoprecipitation assays. RNA interference-mediated inhibition of CDX2 decreased endogenous MDR1 expression. In various colorectal cancer cell lines and human tissues, endogenous MDR1 expression was well correlated to CDX2 expression. Over-expression of CDX2 in HT-29 cells revealed increased resistance to MDR1's known substrate, vincristine and paclitaxel, which was reversed by an MDR1 inhibitor, verapamil. These data indicate that CDX2 directly regulates MDR1 gene expression via binding to elements in the promoter region. Thus, CDX2 is probably important for basal expression of MDR1, regulating drug excretion and absorption in the lower gastrointestinal tract, as well as for multidrug resistance to chemotherapy reagent in CDX2-positive gastrointestinal cancers.

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

“…The multidrug resistance genes MDR1 (also called ABCB1 ) and CFTR (also called ABCC7 ), coding for two ATP‐dependent drug efflux pumps, are transcriptional downstream targets of CDX2 (Kerschner and Harris, 2012; Koh et al ., 2016; Takakura et al ., 2010; Yan et al ., 2015). We found that both MDR1/ABCB1 and CFTR/ABCC7 were significantly downregulated in CDX2‐negative patient tumors and cell lines, independent of MSI status (Fig.…”

Influence of overexpression of efflux proteins on the function and gene expression of endogenous peptide transporters in MDR-transfected MDCKII cell lines

“…One explanation is that transfected exogenous genes may compete with the endogenous genes for binding sites on transcription factors or transcriptional coactivator and corepressor complexes. Recent studies have shown that transcription factors, Sp1 binding sites play a decisive role in the basal expression of MDR1 (human), MRP2 (rat), BCRP (human) and PepT1 (human) (Cornwell and Smith, 1993; Shimakura et al, 2006; Takakura et al, 2010; Zhang et al, 2012; Kauffmann et al, 2001). Competition with highly expressed exogenous genes might trigger the down-regulation of endogenous gene expression in these cells.…”

CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

“…However, little is known about the consequences of aberrant CDX2 expression in hematopoietic cells (12). Whereas the global gene expression patterns regulated by CDX2 have been determined in embryonic stem cells, intestinal cells, and human CRC cells (9,19,21,52,53), previous studies of murine and human AML were limited to selected HOX genes that are known transcriptional targets of CDX2 during development (14)(15)(16).…”