Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma

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Miikkulainen , P , Högel , H , Seyednasrollah , F , Rantanen , K , Elo , L L & Jaakkola , P M 2019 , ' Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma ' , Journal of Biological Chemistry , vol. 294 , no. 10 , pp. 3760-3771 . https://doi.org/10.1074/jbc.RA118.004902

Title: Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma
Author: Miikkulainen, Petra; Högel, Heidi; Seyednasrollah, Fatemeh; Rantanen, Krista; Elo, Laura L.; Jaakkola, Panu M.
Contributor organization: Department of Oncology
Clinicum
University of Helsinki
HUS Comprehensive Cancer Center
Date: 2019-03-08
Language: eng
Number of pages: 12
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
DOI: https://doi.org/10.1074/jbc.RA118.004902
URI: http://hdl.handle.net/10138/314536
Abstract: Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor -subunits (HIF-) and their downstream targets. HIF-2 expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2 protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2 protein and mRNA. Depletion of other PHD family members had no effect on HIF-2 expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2 protein expression. Accordingly, PHD3 knockdown decreased HIF-2 target gene expression in ccRCC cells and expression was restored upon forced HIF-2 expression. The effect of PHD3 depletion was pinpointed to HIF2A mRNA stability. In line with these in vitro results, a strong positive correlation of PHD3 and HIF2A mRNA expression in ccRCC tumors was detected. Our results suggest that in contrast to the known negative regulation of HIF-2 in most cell types, high PHD3 expression in ccRCC cells maintains elevated HIF-2 expression and that of its target genes, which may enhance kidney cancer aggressiveness.
Subject: cancer
cancer biology
hypoxia
hypoxia-inducible factor (HIF)
mRNA decay
ccRCC
Egl-9 family hypoxia-inducible factor 3 (EGLN3)
post-transcriptional regulation
prolyl hydroxylase PHD3
renal cell carcinoma
PROLYL HYDROXYLASES
GENE-EXPRESSION
TRANSCRIPTION
HIF-1-ALPHA
PROTEIN
TRANSLATION
PROTEASOME
STABILITY
CANCER
HIF-1
1182 Biochemistry, cell and molecular biology
3122 Cancers
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion


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