HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia

Flora Cimmino, Marianna Avitabile, Vito Alessandro Lasorsa, Annalaura Montella, Lucia Pezone, Sueva Cantalupo, Feliciano Visconte, Maria Valeria Corrias, Achille Iolascon, Mario Capasso

Research output: Contribution to journalArticle

Abstract

BACKGROUND: HIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors.

METHODS: In this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions.

RESULTS: The analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories.

CONCLUSIONS: These findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor.

Original languageEnglish
Pages (from-to)37
JournalBMC Medical Genetics
Volume20
Issue number1
DOIs
Publication statusPublished - Feb 26 2019

Keywords

  • Cell Differentiation
  • Cell Hypoxia
  • Cell Line, Tumor
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Profiling/methods
  • Gene Regulatory Networks
  • Gene Silencing
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Neuroblastoma/genetics
  • Neurons/cytology
  • Prognosis
  • Sequence Analysis, RNA/methods

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    Cimmino, F., Avitabile, M., Lasorsa, V. A., Montella, A., Pezone, L., Cantalupo, S., Visconte, F., Corrias, M. V., Iolascon, A., & Capasso, M. (2019). HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia. BMC Medical Genetics, 20(1), 37. https://doi.org/10.1186/s12881-019-0767-1