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

Cell Rep. 2019 Nov 5;29(6):1469-1481.e9. doi: 10.1016/j.celrep.2019.09.087.

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.

Keywords: CDK inhibitor; CDK1; DUX4; NF-κB; NFE2L3; cell cycle; colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / secondary
  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • CDC2 Protein Kinase / antagonists & inhibitors*
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Chromatin Immunoprecipitation Sequencing
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / mortality
  • Colonic Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Gene Silencing
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mass Spectrometry
  • Mice
  • Mice, Nude
  • NF-kappa B / metabolism
  • RNA, Small Interfering
  • Signal Transduction / genetics
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transplantation, Heterologous

Substances

  • Basic-Leucine Zipper Transcription Factors
  • DUX4L1 protein, human
  • Homeodomain Proteins
  • NF-kappa B
  • NFE2L3 protein, human
  • RELA protein, human
  • RNA, Small Interfering
  • Transcription Factor RelA
  • CDC2 Protein Kinase
  • CDK1 protein, human

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