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J Clin Invest. 2018 Dec 3;128(12):5620-5633. doi: 10.1172/JCI122383. Epub 2018 Nov 12.

Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.

Author information

1
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
2
Centre for Computational Biology and Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.
3
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Campus, London, United Kingdom.
4
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.

Abstract

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.

KEYWORDS:

Cancer; Cell Biology; Mouse models; Oncogenes; Oncology

PMID:
30300142
PMCID:
PMC6264740
DOI:
10.1172/JCI122383
[Indexed for MEDLINE]
Free PMC Article

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