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<p>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 mechanisms are unclear. Here, we show that complete loss of Cdx1 or concurrent loss of Cdx1/2 increased the stemness and malignancy of intestinal tumors. Consistently, CDX1/2 reduced the expression of cancer stemness-related genes, including <i>LGR5</i>. CDX1/2 bound to the downstream region of the <i>LGR5</i> transcription start site (TSS), a region where β-catenin also binds. Despite increased H3 acetylation and an open chromatin structure, CDX1/2 reduced the occupancy of DRB sensitivity-inducing factor (DSIF), RNA polymerase II-associated factor 1 (PAF1), and RNA polymerase II (Pol II) complexes around the <i>LGR5</i> TSS. Through their homeodomains, CDX1/2 inhibited the β-catenin-facilitated formation of active Pol II complexes containing DSIF and PAF1 complexes by preventing the interaction between β-catenin and these complexes, in an additive manner. Our findings suggest that CDX1/2 cooperatively suppressed colonic tumorigenesis and cancer stemness by antagonizing β-catenin via the DSIF and PAF1 complexes. Additionally, DSIF and PAF1 complexes acted as transcriptional platforms that integrated and funneled both tumor-suppressive and oncogenic signals into the expression of genes that control colon cancer stemness.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月21日

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  • Koji Aoki,
  • Akari Nitta,
  • Ayumi Igarashi

摘要

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 mechanisms are unclear. Here, we show that complete loss of Cdx1 or concurrent loss of Cdx1/2 increased the stemness and malignancy of intestinal tumors. Consistently, CDX1/2 reduced the expression of cancer stemness-related genes, including LGR5. CDX1/2 bound to the downstream region of the LGR5 transcription start site (TSS), a region where β-catenin also binds. Despite increased H3 acetylation and an open chromatin structure, CDX1/2 reduced the occupancy of DRB sensitivity-inducing factor (DSIF), RNA polymerase II-associated factor 1 (PAF1), and RNA polymerase II (Pol II) complexes around the LGR5 TSS. Through their homeodomains, CDX1/2 inhibited the β-catenin-facilitated formation of active Pol II complexes containing DSIF and PAF1 complexes by preventing the interaction between β-catenin and these complexes, in an additive manner. Our findings suggest that CDX1/2 cooperatively suppressed colonic tumorigenesis and cancer stemness by antagonizing β-catenin via the DSIF and PAF1 complexes. Additionally, DSIF and PAF1 complexes acted as transcriptional platforms that integrated and funneled both tumor-suppressive and oncogenic signals into the expression of genes that control colon cancer stemness.