Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis

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 2 alpha (HIF2 alpha), an oncogenic transcription factor implicated in renal tumorigenesis, is known to be degraded by the ubiquitin-proteasome system (UPS). Here, we report that HIF2 alpha is in part constitutively degraded by autophagy. HIF2 alpha interacts with autophagy-lysosome system components. Inhibition of autophagy increases HIF2 alpha, whereas induction of autophagy decreases HIF2 alpha. The E3 ligase von Hippel-Lindau and autophagy receptor protein p62 are required for autophagic degradation of HIF2 alpha. There is a compensatory interaction between the UPS and autophagy in HIF2 alpha degradation. Autophagy inactivation redirects HIF2 alpha to proteasomal degradation, whereas proteasome inhibition induces autophagy and increases the HIF2 alpha-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 HIF2 alpha is a novel tumor suppression mechanism.