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 Article has an altmetric score of 9

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

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 6

The majority of early responding Wnt-activated genes are MYC independent.

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The majority of early responding Wnt-activated genes are MYC independent...
(A) Treatment with ETC-159 for 56 hours reduces the protein abundance of MYC in HPAF-II WT xenografts, but not HPAF-II T58A xenografts. Ratios of MYC levels to β-actin levels for each lane are indicated. (B) The majority of Wnt-activated genes are MYC independent. Wnt-activated genes were classified as either MYC dependent or MYC independent based on whether they responded differently to ETC-159 treatment (interaction test, q value < 10%) across the 3 xenograft models studied (HPAF-II, MYC OE, and MYC T58A). (C) MYC-dependent and -independent Wnt-activated genes in each time-series cluster regulate distinct biological processes (gene ontology: biological process) (hypergeometric test). Annotated WNT target genes (i.e. Wnt signaling and anterior/posterior patterning) are MYC independent. Ribosome biogenesis and cell-cycle genes are regulated both by MYC-dependent and -independent pathways. (D) Representative examples of early responding MYC-independent Wnt-activated target genes. Expression and log2 fold changes in HPAF-II, MYC OE, and MYC T58A xenograft model systems treated with ETC-159 for 56 hours.