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Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation

A M Masudul Azad Chowdhury1, Hiroki Katoh1, Atsushi Hatanaka1

  • 1Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.

Scientific Reports
|October 4, 2017
PubMed

Insights

Nuclear translocation of the transcription factor NRF3 (NFE2L3) is crucial for cancer cell proliferation. This study reveals NRF3

Area of Science:

  • Molecular biology
  • Cancer research
  • Cellular signaling

Background:

  • The transcription factor NRF3 (NFE2L3) plays a role in cancer, but its nuclear translocation and target genes are poorly understood.
  • Under physiological conditions, NRF3 is sequestered in the endoplasmic reticulum (ER) and subject to degradation.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating NRF3 nuclear translocation and its role in cancer cell proliferation.
  • To identify the target genes modulated by NRF3 in cancer cells.

Main Methods:

  • Investigated NRF3 degradation pathways in cytoplasm and nucleus using ubiquitin ligases HRD1, VCP, and β-TRCP.
  • Utilized the aspartic protease DDI2 to study NRF3 nuclear translocation from the ER.
  • Analyzed NRF3-mediated gene expression of UHMK1 in relation to cell proliferation.

Main Results:

  • NRF3 is degraded in the cytoplasm by HRD1/VCP and in the nucleus by β-TRCP.
  • Nuclear translocation of NRF3 from the ER is dependent on DDI2, independent of HRD1/VCP degradation.
  • NRF3 regulates U2AF homology motif kinase 1 (UHMK1) gene expression, promoting cell proliferation.

Conclusions:

  • NRF3 activity is multiply regulated, impacting cancer cell proliferation.
  • DDI2 is essential for NRF3 nuclear translocation, while degradation pathways involve HRD1, VCP, and β-TRCP.
  • NRF3's regulation of UHMK1 is a key mechanism driving cancer cell proliferation.

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