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

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

doi:10.1186/s12881-019-0767-1

Abstract

BackgroundHIF1A (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.MethodsIn 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.ResultsThe 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.ConclusionsThese 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.

Highlights

HIF-1α mRNA (HIF1A) (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches
HIF1A expression by the use of two short hairpin against HIF1A (SKNBE2 SHSY5Y cells were depleted for HIF1A expression (shHIF1A)#A and SKNBE2 shHIF1A#B) and were grown in normoxia and hypoxia conditions (NX and HYP); unsilenced cells were used as control (SKNBE2 shCTR) (Fig. 1a)
Small changes of global expression levels were observed in the four conditions (Additional file 2: Figure S2B), principal component analysis (PCA) and multi-dimensional scaling (MDS) highlighted the important role of oxygen in separating shCTR HYP and shCTR NX whereas shHIF1A NX and shHIF1A HYP showed highly similar profiles in PCA analysis (Additional file 2: Figure S2C and D)

Summary

Introduction

HIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. 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. Low oxygen levels represent an important microenvironment condition to affect the activation status of signaling pathways as drug resistance mechanism. The increased expression of Hypoxia-Inducible-Factor HIF-1α mRNA (HIF1A) in tumors is relevant to establish resistance to therapeutic approaches as radiotherapy [10, 11]. We have recently reported that high HIF1A expression may stratify high-risk NB patients with poorer prognosis and low HIF1A expression enhances neuronal differentiation signaling pathways activation and response to differentiating agents [12]. Conditions with increased availability of glucose, such as diabetes or down-regulation of GLOI highlight the importance of mechanisms to disrupt cell response to hypoxia

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