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Dev Cell. 2018 Mar 12;44(5):582-596.e4. doi: 10.1016/j.devcel.2018.02.010.

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

Author information

1
Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Center for Cardiovascular Regeneration, Houston Methodist Hospital Research Institute, Houston, TX, USA; Department of Cardiothoracic Surgery, Weill Cornell Medical College, Cornell University, New York, NY, USA.
3
Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and Health Science Center, Houston, TX 77030, USA; Program in Genetics and Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jaeil@mdanderson.org.

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.

KEYWORDS:

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

PMID:
29533773
PMCID:
PMC5854208
DOI:
10.1016/j.devcel.2018.02.010
[Indexed for MEDLINE]
Free PMC Article

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