Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis

• Published in: Oncogene Vol. 34; no. 19; pp. 2450 - 2460
• Main Authors: Liu, X-D, Yao, J, Tripathi, D N, Ding, Z, Xu, Y, Sun, M, Zhang, J, Bai, S, German, P, Hoang, A, Zhou, L, Jonasch, D, Zhang, X, Conti, C J, Efstathiou, E, Tannir, N M, Eissa, N T, Mills, G B, Walker, C L, Jonasch, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.05.2015; Nature Publishing Group
• Subjects: 13/51; 14/1; 14/35; 14/63; 38/77; 38/90; 631/67; 631/67/589/1588/1351; 631/80/474/2085; 631/80/82/39; 692/420/755; 82/29; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Analysis; Apoptosis; Apoptosis Regulatory Proteins - genetics; Autophagy; Autophagy - genetics; Autophagy-Related Protein 7; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Beclin-1; Carcinoma, Renal cell; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Clear cell-type renal cell carcinoma; Diagnosis; Genetic transcription; Health aspects; HEK293 Cells; Human Genetics; Humans; Hypoxia-inducible factors; Internal Medicine; Kidney; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Lysosomes; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Neoplasia; Oncology; Organelles; original-article; Phagocytosis; Proteasomes; Proteins; RNA Interference; RNA, Small Interfering; Sequestosome-1 Protein; Tumor suppression; Tumorigenesis; Ubiquitin; Ubiquitin-Activating Enzymes - genetics; Ubiquitin-proteasome system; Ubiquitin-protein ligase; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.199

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.