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

Marina Bury, Benjamin Le Calve, Frédéric Lessard, Thomas Dal Maso, James Saliba, Carine Michiels, Gerardo Febeyre, Blank Vloker

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Abstract

Constitutive nuclear factor κB (NF-κB) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-κB signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-κB and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy.

Original languageEnglish
Pages (from-to)1469-1481.e9
JournalCell Reports
Volume29
Issue number6
DOIs
Publication statusPublished - 5 Nov 2019

Keywords

  • NFE2L3
  • NF-κB
  • DUX4
  • CDK1
  • Cell cycle
  • colorectal cancer
  • CDK inhibitor
  • cell cycle

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