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Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas

Takahiro Isono1, Tokuhiro Chano2, Tetsuya Yoshida3

  • 1Central Research Laboratory, Shiga University of Medical Science Otsu, Shiga 520-2192, Japan.

American Journal of Cancer Research
|November 9, 2016
PubMed

Insights

Deprivation-resistant renal cell carcinoma (RCC) cells show enhanced hypoxia-inducible factors (HIF). Targeting hydroxyl-HIF2-alpha, identified through transcriptional analysis, may offer a new therapeutic strategy for resistant RCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Dormant cancer cells, including those in renal cell carcinoma (RCC), are often deprivation-resistant, posing significant challenges to cancer therapy.
  • This resistance limits the effectiveness of various treatment modalities for RCC patients.

Purpose of the Study:

  • To transcriptionally characterize deprivation-resistant RCC cells using next-generation sequencing.
  • To identify potential molecular targets for overcoming treatment resistance in RCC.

Main Methods:

  • Next-generation sequencing was employed to identify transcriptional differences in deprivation-resistant RCC cells.
  • Gene expression analysis focused on hypoxia-inducible factors (HIF) and related pathways.
  • Functional studies involved gene knockdown (HIF2-alpha, HIF1-alpha) and treatment with a HIF inhibitor (Chetomin).

Main Results:

  • Deprivation-resistant RCCs exhibited a significantly enhanced hypoxia-inducible factor (HIF) transcription factor network compared to sensitive RCCs.
  • Loss of Von Hippel-Lindau tumor suppressor expression correlated with nuclear hydroxyl-HIF2-alpha expression in resistant cells.
  • Knockdown of HIF2-alpha, but not HIF1-alpha, induced cell death and reduced HIF-related gene expression.
  • The HIF inhibitor Chetomin demonstrated significant cytotoxicity in deprivation-resistant RCC cells.

Conclusions:

  • Hydroxyl-HIF2-alpha is upregulated in deprivation-resistant RCC and may play a critical role in cell survival.
  • Targeting hydroxyl-HIF2-alpha presents a promising therapeutic strategy for overcoming treatment resistance in renal cell carcinoma.
Keywords:
HIF2-alphaHypoxia-inducible factors (HIF)POU5F1Von Hippel-Lindau (VHL)chetomindeprivationglobal transcriptomehydroxyl-HIF-alphanext generation sequencer (NGS)renal cell carcinoma (RCC)

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