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NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

Marina Bury1, Benjamin Le Calvé2, Frédéric Lessard2

  • 1Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada.

Cell Reports
|November 7, 2019
PubMed

Insights

Nuclear factor κB (NF-κB) signaling drives colon cancer by regulating NFE2L3, which controls cyclin-dependent kinase 1 (CDK1) activity. Inhibiting NFE2L3 suppresses tumor growth, offering new therapeutic targets for colon adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Constitutive nuclear factor κB (NF-κB) activation is a key driver of colon tumor growth.
  • Cyclin-dependent kinases (CDKs) are crucial for cell-cycle regulation and represent a target for anticancer therapies.

Purpose of the Study:

  • To elucidate the role of the transcription factor NFE2L3 in the NF-κB signaling pathway and its impact on colon cancer proliferation.
  • To investigate the link between NF-κB, NFE2L3, and cyclin-dependent kinase 1 (CDK1) activity in colon adenocarcinoma.

Main Methods:

  • Investigated the regulation of NFE2L3 by the RELA subunit of NF-κB.
  • Analyzed NFE2L3 expression levels in colon adenocarcinoma patients versus normal tissue.
  • Performed NFE2L3 silencing in vitro and in vivo to assess effects on cell proliferation and tumor growth.
  • Examined the impact of NFE2L3 knockdown on double homeobox factor 4 (DUX4) and CDK1 levels.

Main Results:

  • NFE2L3 expression is regulated by NF-κB's RELA subunit and is elevated in colon adenocarcinoma.
  • Silencing NFE2L3 significantly reduces colon cancer cell proliferation in vitro and tumor growth in vivo.
  • NFE2L3 knockdown leads to increased levels of DUX4, a direct inhibitor of CDK1.

Conclusions:

  • NFE2L3 acts as a critical regulator linking NF-κB signaling to CDK1 activity, promoting colon cancer cell proliferation.
  • The identified NFE2L3-DUX4-CDK1 pathway presents a novel target for precision therapy in colon cancer.
Keywords:
CDK inhibitorCDK1DUX4NF-κBNFE2L3cell cyclecolorectal cancer

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