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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 9

Wnt and MYC coregulate ribosome biogenesis.

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Wnt and MYC coregulate ribosome biogenesis.
(A) Wnt inhibition reduces n...
(A) Wnt inhibition reduces nucleoli, but this is rescued by expression of stabilized MYC. Changes in nucleolar size and abundance in tumor sections was assessed by silver staining. (B) Expression of ribosomal subunit genes (RPLs/RPSs) is enhanced by stabilized MYC T58A, but remains sensitive to PORCN inhibition. The outlier in HPAF-II tumors is RPS27L, as in Figure 8A. (C) Representative Wnt-activated ribosome biogenesis genes that are MYC dependent. Changes in selected genes in MYC OE and T58A tumors are shown. Relative expression is plotted as TPM (top panels) or as log2 fold change (bottom panels).
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