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

Moon Jong Kim1, Bo Xia2, Han Na Suh1

  • 1Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Developmental Cell
|March 14, 2018
PubMed

Insights

The PCNA-associated factor (PAF) controls self-renewing cells in the intestine. PAF is crucial for intestinal regeneration and tumor growth by regulating Myc expression and Wnt/β-catenin signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mechanisms controlling self-renewing cells in tissue regeneration and cancer are not fully understood.
  • PCNA-associated factor (PAF) is known to modulate DNA repair and activate Wnt/β-catenin signaling.
  • PAF expression is observed in intestinal stem and progenitor cells (ISCs and IPCs).

Purpose of the Study:

  • To investigate the role of PAF in intestinal regeneration and tumorigenesis.
  • To elucidate the molecular mechanisms by which PAF regulates self-renewing cells.
  • To determine the relationship between PAF, Myc, and Wnt/β-catenin signaling in the intestine.

Main Methods:

  • Utilized genetic ablation of PAF in mouse models.
  • Assessed intestinal regeneration following radiation injury.
  • Analyzed intestinal tumorigenesis driven by Apc inactivation.
  • Performed transcriptome profiling and promoter occupancy studies.
  • Examined Myc expression and Wnt/β-catenin signaling activity.

Main Results:

  • PAF is upregulated in intestinal regeneration and tumorigenesis.
  • PAF ablation impairs intestinal regeneration and reduces ISC/IPC populations by affecting Myc expression.
  • PAF directly binds and transactivates the c-Myc promoter, driving ISC/IPC expansion.
  • PAF knockout inhibits Apc-driven intestinal tumorigenesis, reducing tumor stemness and Wnt/β-catenin signaling.

Conclusions:

  • The PAF-Myc signaling axis is essential for intestinal regeneration and tumorigenesis.
  • PAF positively regulates self-renewing cells in the intestine through Myc and Wnt/β-catenin pathways.
  • Targeting the PAF-Myc axis may offer therapeutic strategies for intestinal regeneration and cancer treatment.
Keywords:
MycPAFWnt signalingcancer stem cellscolorectal cancerintestinal regenerationintestinal stem cellsstem/progenitor cellsβ-catenin

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