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Oncogene. 2015 May 7;34(19):2450-60. doi: 10.1038/onc.2014.199. Epub 2014 Jul 7.

Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis.

Author information

1
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
4
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
6
Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Houston, TX, USA.

Abstract

Autophagy is a conserved process involved in lysosomal degradation of protein aggregates and damaged organelles. The role of autophagy in cancer is a topic of intense debate, and the underlying mechanism is still not clear. The hypoxia-inducible factor 2α (HIF2α), an oncogenic transcription factor implicated in renal tumorigenesis, is known to be degraded by the ubiquitin-proteasome system (UPS). Here, we report that HIF2α is in part constitutively degraded by autophagy. HIF2α interacts with autophagy-lysosome system components. Inhibition of autophagy increases HIF2α, whereas induction of autophagy decreases HIF2α. The E3 ligase von Hippel-Lindau and autophagy receptor protein p62 are required for autophagic degradation of HIF2α. There is a compensatory interaction between the UPS and autophagy in HIF2α degradation. Autophagy inactivation redirects HIF2α to proteasomal degradation, whereas proteasome inhibition induces autophagy and increases the HIF2α-p62 interaction. Importantly, clear-cell renal cell carcinoma (ccRCC) is frequently associated with monoallelic loss and/or mutation of autophagy-related gene ATG7, and the low expression level of autophagy genes correlates with ccRCC progression. The protein levels of ATG7 and beclin 1 are also reduced in ccRCC tumors. This study indicates that autophagy has an anticancer role in ccRCC tumorigenesis, and suggests that constitutive autophagic degradation of HIF2α is a novel tumor suppression mechanism.

PMID:
24998849
PMCID:
PMC4286517
DOI:
10.1038/onc.2014.199
[Indexed for MEDLINE]
Free PMC Article

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