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Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis
Babita Madan, … , Enrico Petretto, David M. Virshup
Babita Madan, … , Enrico Petretto, David M. Virshup
Published October 9, 2018
Citation Information: J Clin Invest. 2018;128(12):5620-5633. https://doi.org/10.1172/JCI122383.
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Research Article Cell biology Oncology

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

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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.

Authors

Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup

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Figure 8

PORCN inhibition leads to a reduction in expression of key ribosome biogenesis genes.

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PORCN inhibition leads to a reduction in expression of key ribosome biog...
(A) Coherent changes in the expression of genes encoding ribosomal proteins (RPLs/RPSs) over time following PORCN inhibition. (B) Coherent changes in the abundance of ribosomal proteins over time as assessed by mass spectrometry following PORCN inhibition. (C) Coherent changes in the expression of nucleoporin genes over time following PORCN inhibition. (D) Gene expression of RNA polymerases subunits, including POLR1B and POLR3G, that transcribe ribosomal RNA are Wnt regulated. (E) Key regulators of ribosome biogenesis NPM1, BOP1, NUP58, and DKC1 change over time following PORCN inhibition.
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