Neddylation blockade induces HIF-1α driven cancer cell migration via upregulation of ZEB1

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Jun Bum Park1,2, Jieun Seo1,2, Jong-Wan Park1,2

  • 1Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Korea.

Scientific Reports
|October 24, 2020
PubMed

Insights

Neddylation inhibition activates hypoxia-inducible factor 1α (HIF-1α) via the PI3K-Akt pathway. This regulates the epithelial to mesenchymal transition (EMT) activator ZEB1, impacting cancer cell migration and metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Neddylation, the conjugation of NEDD8 to proteins, is increasingly recognized for its role in cancer cell migration.
  • The epithelial to mesenchymal transition (EMT) is a critical process in cancer invasion and metastasis, but neddylation's role in EMT remains unclear.
  • Previous research linked neddylation to cancer cell migration via the PI3K-Akt pathway.

Purpose of the Study:

  • To elucidate the mechanistic details of neddylation's role in the EMT process.
  • To investigate the relationship between neddylation, hypoxia-inducible factor 1α (HIF-1α), and ZEB1 in cancer cell lines.
  • To understand how neddylation impacts cancer cell migration through the PI3K-Akt pathway.

Main Methods:

  • Inhibition of neddylation in various cancer cell lines.
  • Analysis of the PI3K-Akt pathway activation.
  • Assessment of hypoxia-inducible factor 1α (HIF-1α) and ZEB1 expression levels.

Main Results:

  • Inhibiting neddylation activates HIF-1α through the PI3K-Akt pathway.
  • Activated HIF-1α subsequently regulates the EMT-activator ZEB1.
  • These findings establish a link between neddylation, HIF-1α, and ZEB1 in the context of cancer cell migration.

Conclusions:

  • Neddylation plays a significant role in regulating cancer cell migration by influencing the HIF-1α/ZEB1 axis.
  • Understanding this pathway provides new insights into metastasis mechanisms.
  • Targeting neddylation could offer novel therapeutic strategies for cancer treatment.

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