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

Nathan Harmston1,2, Jun Yi Stanley Lim1, Oriol Arqués3

  • 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.

Cancer Research
|November 18, 2020
PubMed

Insights

Aberrant Wnt signaling in cancer represses MAPK activity, promoting proliferation. Inhibiting Wnt signaling activates MAPK, revealing a dual role in gene regulation and cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Aberrant Wnt signaling is a known driver of various cancers, influencing proto-oncogenes like MYC and cyclins.
  • Previous understanding focused on Wnt/β-catenin's role in gene activation, but its broader transcriptomic impact was unclear.

Purpose of the Study:

  • To investigate genes upregulated upon Wnt signaling inhibition in pancreatic and colorectal cancer models.
  • To elucidate the role of Wnt signaling in repressing MAPK activity and its implications for cancer proliferation.

Main Methods:

  • Examined gene expression changes in response to Wnt signaling inhibition in cancer models.
  • Assessed the impact of concurrent MEK inhibition on Wnt-mediated gene expression changes.

Main Results:

  • Inhibition of Wnt signaling led to increased gene expression via activation of ERK and JNK pathways.
  • Concurrent MEK inhibition partially reversed these gene expression changes.
  • Wnt signaling was found to repress MAPK activity, preventing RAS-mediated senescence and promoting cancer cell proliferation.

Conclusions:

  • Wnt/β-catenin signaling plays a dual role, activating some genes while repressing others, including those involved in MAPK signaling.
  • Wnt signaling fine-tunes the RAS-MAPK pathway to optimize cancer cell proliferation by suppressing senescence.
  • This study reframes Wnt/β-catenin signaling as a critical regulator of both gene activation and repression in cancer.

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