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Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway.

Publication ,  Journal Article
Harmston, N; Lim, JYS; Arqués, O; Palmer, HG; Petretto, E; Virshup, DM; Madan, B
Published in: Cancer Res
January 15, 2021

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. SIGNIFICANCE: These findings show that Wnt/β-catenin signaling causes widespread gene repression via inhibition of MAPK signaling, thus fine tuning the RAS-MAPK pathway to optimize proliferation in cancer.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 15, 2021

Volume

81

Issue

2

Start / End Page

464 / 475

Location

United States

Related Subject Headings

  • beta Catenin
  • Xenograft Model Antitumor Assays
  • Wnt1 Protein
  • Tumor Cells, Cultured
  • Pyrimidinones
  • Pyridones
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinases
  • Mice, SCID
 

Citation

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Harmston, N., Lim, J. Y. S., Arqués, O., Palmer, H. G., Petretto, E., Virshup, D. M., & Madan, B. (2021). Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway. Cancer Res, 81(2), 464–475. https://doi.org/10.1158/0008-5472.CAN-20-2129
Harmston, Nathan, Jun Yi Stanley Lim, Oriol Arqués, Héctor G. Palmer, Enrico Petretto, David M. Virshup, and Babita Madan. “Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway.Cancer Res 81, no. 2 (January 15, 2021): 464–75. https://doi.org/10.1158/0008-5472.CAN-20-2129.
Harmston N, Lim JYS, Arqués O, Palmer HG, Petretto E, Virshup DM, et al. Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway. Cancer Res. 2021 Jan 15;81(2):464–75.
Harmston, Nathan, et al. “Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway.Cancer Res, vol. 81, no. 2, Jan. 2021, pp. 464–75. Pubmed, doi:10.1158/0008-5472.CAN-20-2129.
Harmston N, Lim JYS, Arqués O, Palmer HG, Petretto E, Virshup DM, Madan B. Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway. Cancer Res. 2021 Jan 15;81(2):464–475.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 15, 2021

Volume

81

Issue

2

Start / End Page

464 / 475

Location

United States

Related Subject Headings

  • beta Catenin
  • Xenograft Model Antitumor Assays
  • Wnt1 Protein
  • Tumor Cells, Cultured
  • Pyrimidinones
  • Pyridones
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinases
  • Mice, SCID