Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.
Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent signaling pathways in an orthotopic model of Wnt-addicted pancreatic cancer, using a porcupine (PORCN) inhibitor currently in clinical trials, and validated key results in additional Wnt-addicted models. The temporal analysis of the drug-perturbed transcriptome demonstrated direct and indirect regulation of more than 3,500 Wnt-activated genes (23% of the transcriptome). Regulation was both via Wnt/β-catenin and through the modulation of protein abundance of important transcription factors, including MYC, via Wnt-dependent stabilization of proteins (Wnt/STOP). Our study identifies a central role of Wnt/β-catenin and Wnt/STOP signaling in controlling ribosome biogenesis, a key driver of cancer proliferation.
Duke Scholars
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Related Subject Headings
- Wnt Signaling Pathway
- Transcriptome
- Ribosomes
- Proto-Oncogene Proteins c-myc
- Protein Stability
- Pancreatic Neoplasms
- Neoplasms, Experimental
- Mice, SCID
- Mice, Inbred NOD
- Mice
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Wnt Signaling Pathway
- Transcriptome
- Ribosomes
- Proto-Oncogene Proteins c-myc
- Protein Stability
- Pancreatic Neoplasms
- Neoplasms, Experimental
- Mice, SCID
- Mice, Inbred NOD
- Mice