PAF-Myc controls the proliferation of self-renewing cells during intestinal regeneration and tumorigenesis
The underlying mechanisms how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. Independently of PCNA interaction, PAF is physically and functionally associated with Wnt/β-catenin signaling. 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 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 PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells.
Kim et al., Developmental Cell 44 (5):582-596, 3/2018. (PDF)