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CDX1 and CDX2 suppress colon cancer stemness by inhibiting b-catenin-facilitated formation of Pol II–DSIF–PAF1C complex

ABSTRACT: Gene expression profiles of DLD1-TetOff cells comparing control TetOff cells with TetOff cells expressing Cdx1 or Cdx2 for 12 and 24 hours.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287318 | GEO | 2025/04/29

REPOSITORIES: GEO

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CDX1 and CDX2 suppress colon cancer stemness by inhibiting beta-catenin-facilitated formation of Pol II-DSIF-PAF1C complex

Project description:Homeobox transcription factors CDX1 and CDX2 (hereafter, CDX1/2) play key roles in determining the identity of intestinal epithelial cells and regulating their stem cell functions. However, the role of CDX1/2 in regulating colon cancer stemness and the underlying mechanism have been unclear. Here, we show that the complete loss of Cdx1 or concurrent loss of Cdx1/2 increased the stemness and malignancy of intestinal tumors. Consistently, CDX1/2 reduced the expression levels of cancer stemness-related genes including LGR5. CDX1/2 bound to the downstream region of the LGR5 transcription start site (TSS), where b-catenin also binds. Despite increased H3 acetylation and an open chromatin structure, CDX1/2 reduced the levels of DRB sensitivity-inducing factor (DSIF), RNA polymerase II-associated factor 1 (PAF1), and Pol II complexes around the LGR5 TSS. Through a homeodomain, CDX1/2 cooperatively inhibited the b-catenin-promoted formation of the active Pol II complex containing DSIF and PAF1 complexes by preventing interactions between b-catenin and these complexes, in an additive manner. Our findings suggest that CDX1/2 cooperatively suppress colonic tumorigenesis and cancer stemness by antagonizing b-catenin through the DSIF and PAF1 complexes. Additionally, DSIF and PAF1 complexes act as transcriptional platforms that integrate both tumor-suppressive and oncogenic signals into the expression of genes that controls colonic tumorigenesis.

2025-04-29 | GSE287500 | GEO

CDX1 and CDX2 suppress colon cancer stemness by inhibiting beta-catenin-facilitated formation of Pol II-DSIF-PAF1C complex

Project description:CDX1 and CDX2 suppress colon cancer stemness by inhibiting beta-catenin-facilitated formation of Pol II-DSIF-PAF1C complex

| PRJNA1213101 | ENA

CDX1 and CDX2 suppress colon cancer stemness by inhibiting b-catenin-facilitated formation of Pol II–DSIF–PAF1C complex

Project description:CDX1 and CDX2 suppress colon cancer stemness by inhibiting b-catenin-facilitated formation of Pol II–DSIF–PAF1C complex

| PRJNA1212081 | ENA

Cdx2 transcription factor binding in intestinal villus and gene expression profiling in Cdx mutant mice

Project description:We conditionally inactivated mouse Cdx2, a dominant regulator of intestinal development, and mapped its genome occupancy in adult intestinal villi. Although homeotic transformation, observed in Cdx2-null embryos, was absent in mutant adults, gene expression and cell morphology were vitally compromised. Lethality was accelerated in mice lacking both Cdx2 and its homolog Cdx1, with exaggeration of defects in crypt cell replication and enterocyte differentiation. Cdx2 occupancy correlated with hundreds of transcripts that fell but not with equal numbers that rose with Cdx loss, indicating a predominantly activating role at intestinal cis-regulatory regions. Integrated consideration of a mutant phenotype and cistrome hence reveals the continued and distinct requirement in adults of a master developmental regulator that activates tissue-specific genes. Cdx2 ChIP-seq in mouse villus, and gene expression data from Cdx1, Cdx2 and compound knockout mouse intestine

2011-04-13 | E-GEOD-24633 | biostudies-arrayexpress

Comparison of ectopic gene expression in Cdx1+/+ and Cdx1-/- thymic medullary epithelial cells

Project description:We have found that Cdx1 can promote ectopic gene expression in thymic epithelial cells. We isolated MHCIIhi CD80hi medullary thymic epithelial cells from Cdx1-/- and Cdx1+/+ and compare gene expression between the two subsets, also in the context of Cdx1-mediated changes in intestinal epithelial cells.

2018-05-01 | GSE68880 | GEO

Cdx2 transcription factor binding in intestinal villus and gene expression profiling in Cdx mutant mice

2011-04-13 | GSE24633 | GEO

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Project description:This study is to identify downstream targets of homeobox gene CDX1. The study assayed the expression of 2 pairs of stably transfected colorectal cancer cell lines: The CDX1 nonexpressing CRC cell line HCT116 was stably transfected with either CDX1 cDNA in the pRC/CMV expression vector (HCT116-CDX1) or with vector control (HCT116-Vec). The CDX1-expressing CRC cell line LS174T was similarly transfected with either a pSilencer vector containing a short sequence of CDX1 siRNA (LS174T-siRNA) , or a pSilencer vector containing a scrambled siRNA sequence as a control (LS174T-Vec).

2009-01-13 | GSE14380 | GEO

Gene expression data and CDX1-binding sites in gastric epithelial cells

Project description:To identify the transcriptional targets of CDX1 underlying the metaplastic change, we explored genes affected by ectopic expression of CDX1 in gastric epithelial cells by combining expression microarray and ChIP-chip analyses.

2012-10-18 | GSE35369 | GEO

Transcription profiling of human colorectal cancer cell lines transfected with homeobox gene CDX1 cDNA to identfiy downstream targets

2009-01-23 | E-GEOD-14380 | biostudies-arrayexpress

Cdx1 and Cdx2 exhibit transcriptional specificity in the intestine.

Project description:The caudal-related homeodomain transcription factors Cdx1 and Cdx2 are expressed in the developing endoderm with expression persisting into adulthood. Cdx1(-/-) mutants are viable and fertile and display no overt intestinal phenotype. Cdx2 null mutants are peri-implantation lethal; however, conditional mutation approaches have revealed that Cdx2 is required for patterning the intestinal epithelium and specification of the colon. Cdx2 is also necessary for homeostasis of the intestinal tract in the adult, where Cdx1 and Cdx2 appear to functionally overlap in the distal colon, but not during intestinal development. Cdx1 and Cdx2 exhibit complete overlap of expression in the intestine, although they differ in their relative levels, with Cdx1 maximal in the distal colon and Cdx2 peaking in the proximal cecum. Moreover, Cdx1 protein is graded along the crypt-villus axis, being abundant in the crypts and diminishing towards the villi. Cdx2 is expressed uniformly along this axis, but is differentially phosphorylated; the functional relevance of these expression domains and phosphorylation is currently unknown. Cdx1 and Cdx2 have been suggested to exhibit functional specificity in the intestinal tract. In the present study, using cell-based models, we found that relative to Cdx1, Cdx2 was significantly less potent at effecting a transcriptional response from the Cdx1 promoter, a known Cdx target gene. We subsequently assessed this relationship in vivo using a "gene swap" approach and found that Cdx2 cannot substitute for Cdx1 in this autoregulatory loop. This is in marked contrast with the ability of Cdx2 to support Cdx1 expression and function in paraxial mesoderm and vertebral patterning, thus providing novel in vivo evidence of context-dependent transcriptional specificity between these transcription factors.

| S-EPMC3559873 | biostudies-literature

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