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Widespread repression of gene expression in cancer by a Wnt/β-Catenin/MAPK pathway

Harmston, Nathan, Lim, Stanley Yi Jun, Arqués, Oriel, Palmer, Hector G., Petretto, Enrico, Virshup, David M. and Madan, Babita 2021. Widespread repression of gene expression in cancer by a Wnt/β-Catenin/MAPK pathway. Cancer Research 81 (2) , pp. 464-475. 10.1158/0008-5472.CAN-20-2129

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Aberrant Wnt signaling drives a number of cancers through regulation of diverse downstream pathways. Wnt/β-catenin signaling achieves this in part by increasing the expression of proto-oncogenes such as MYC and cyclins. However, global assessment of the Wnt-regulated transcriptome in vivo in genetically distinct cancers demonstrates that Wnt signaling suppresses the expression of as many genes as it activates. In this study, we examined the set of genes that are upregulated upon inhibition of Wnt signaling in Wnt-addicted pancreatic and colorectal cancer models. Decreasing Wnt signaling led to a marked increase in gene expression by activating ERK and JNK; these changes in gene expression could be mitigated in part by concurrent inhibition of MEK. These findings demonstrate that increased Wnt signaling in cancer represses MAPK activity, preventing RAS-mediated senescence while allowing cancer cells to proliferate. These results shift the paradigm from Wnt/β-catenin primarily as an activator of transcription to a more nuanced view where Wnt/β-catenin signaling drives both widespread gene repression and activation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Date of Acceptance: 12 November 2020
Last Modified: 05 Sep 2023 11:25

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