PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis

Moon Jong Kim, Bo Xia, Han Na Suh, Sung Ho Lee, Sohee Jun, Esther M. Lien, Jie Zhang, Kaifu Chen, Jae Il Park

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/β-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation injury, genetic ablation of PAF impairs intestinal regeneration along with the severe loss of ISCs and Myc expression. Mechanistically, PAF conditionally occupies and transactivates the c-Myc promoter, which induces the expansion of ISCs/IPCs during intestinal regeneration. In mouse models, PAF knockout inhibits Apc inactivation-driven intestinal tumorigenesis with reduced tumor cell stemness and suppressed Wnt/β-catenin signaling activity, supported by transcriptome profiling. Collectively, our results unveil that the PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells. Controlling the proliferation of self-renewing cells is crucial for tissue homeostasis and regeneration. Kim et al. show that PAF (PCNA-associated factor), dispensable for intestinal homeostasis, is required to positively regulate the proliferation of self-renewing cells via Myc transactivation during intestinal regeneration and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)582-596.e4
JournalDevelopmental Cell
Volume44
Issue number5
DOIs
StatePublished - Mar 12 2018

Keywords

  • Myc
  • PAF
  • Wnt signaling
  • cancer stem cells
  • colorectal cancer
  • intestinal regeneration
  • intestinal stem cells
  • stem/progenitor cells
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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