Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis
Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
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Research Article Cell biology Oncology

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.