Positive feedback loop and synergistic effects between hypoxia-inducible factor-2α and stearoyl-CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma

Cancer Sci. 2013 Apr;104(4):416-22. doi: 10.1111/cas.12108. Epub 2013 Mar 3.

Abstract

Adapting to hypoxic stress is pivotal in tumor progression and determining tumor malignancy. The transcriptional factor hypoxia-inducible factor (HIF) is crucial in modulating tumorous hypoxic responses through altering cell energy metabolism, which includes the modification of glucose and lipid metabolism-associated gene expression. Stearoyl-CoA desaturase-1 (SCD1) is the main isoform of SCDs, the rate-limiting enzymes in the biosynthesis of monounsaturated fatty acids from saturated fatty acids, which is extensively activated in cancer progression. In this study, we found that SCD1 and HIF-2α were overexpressed in human clear cell renal cell carcinoma (ccRCC) tissues and ccRCC cell lines, and were upregulated in the 786-0 ccRCC cell line under hypoxia. Knockdown of SCD1 or HIF-2α impacted the other's expression. Enhancing SCD1 resulted in HIF-2α upregulation, which could be blocked by inhibiting the PI3K/Akt pathway. Deficiency of SCD1 or HIF-2α in 768-0 cells led to apoptosis, less colony formation ability, and decreased cell migration. More obvious effects were observed in 786-0 cells with double SCD1 and HIF-2α knockdown. These results indicate a PI3K/Akt-mediated loop between SCD1 and HIF-2α that mutually enhances their protein levels. Both SCD1 and HIF-2α are critical to promoting tumorigenesis by synergistically acting on maintaining cell survival, triggering cell migration, and enhancing the colony formation ability of cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Carcinoma, Renal Cell / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms / metabolism*
  • Oncogene Protein v-akt
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction
  • Stearoyl-CoA Desaturase / metabolism*
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • endothelial PAS domain-containing protein 1
  • Stearoyl-CoA Desaturase
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt