Differential regulation of HIF-1α and HIF-2α in neuroblastoma: Estrogen-related receptor alpha (ERRα) regulates HIF2A transcription and correlates to poor outcome.
Hypoxia-inducible factors (HIFs) are differentially regulated in tumor cells. While the current paradigm supports post-translational regulation of the HIF-α subunits, we recently showed that hypoxic HIF-2α is also transcriptionally regulated via insulin-like growth factor (IGF)-II in the childhood tumor neuroblastoma. Here, we demonstrate that transcriptional regulation of HIF-2α seems to be restricted to neural cell-derived tumors, while HIF-1α is canonically regulated at the post-translational level uniformly across different tumor forms. Enhanced expression of HIF2A mRNA at hypoxia is due to de novo transcription rather than increased mRNA stability, and chemical stabilization of the HIF-α proteins at oxygen-rich conditions unexpectedly leads to increased HIF2A transcription. The enhanced HIF2A levels do not seem to be dependent on active HIF-1. Using a transcriptome array approach, we identified members of the Peroxisome proliferator-activated receptor gamma coactivator (PGC)/Estrogen-related receptor (ERR) complex families as potential regulators of HIF2A. Knockdown or inhibition of one of the members, ERRα, leads to decreased expression of HIF2A, and high expression of the ERRα gene ESRRA correlates with poor overall and progression-free survival in a clinical neuroblastoma material consisting of 88 tumors. Thus, targeting of ERRα and pathways regulating transcriptional HIF-2α are promising therapeutic avenues in neuroblastoma.
Lund University, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Building 406, SE-223 81 Lund, Sweden.
Arash
A
Hamidian
Lund University, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Building 406, SE-223 81 Lund, Sweden.
Kristoffer
K
von Stedingk
Lund University, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Building 406, SE-223 81 Lund, Sweden.
Matilda
M
Munksgaard Thorén
Lund University, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Building 406, SE-223 81 Lund, Sweden.
Sofie
S
Mohlin
Lund University, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Building 406, SE-223 81 Lund, Sweden. Electronic address: sven.pahlman@med.lu.se.
Sven
S
Påhlman
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D016896:Treatment Outcome; D000097983:ERRalpha Estrogen-Related Receptor; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
ERRα; HIF-2α; Hypoxia; Neuroblastoma; Transcription