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Published on: June 3, 2016
Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis
X-D Liu1, J Yao2, D N Tripathi3
1Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 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.
Insights
Autophagy degrades the oncogenic factor hypoxia-inducible factor 2α (HIF2α). This process acts as a tumor suppressor in clear-cell renal cell carcinoma (ccRCC), revealing a new mechanism against cancer progression.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Cancer Research
Background:
- Autophagy is a cellular degradation pathway with a debated role in cancer.
- Hypoxia-inducible factor 2α (HIF2α) is an oncogenic factor driving renal tumors, typically degraded by the ubiquitin-proteasome system (UPS).
Purpose of the Study:
- To investigate the role of autophagy in the degradation of HIF2α.
- To elucidate the mechanism of HIF2α degradation by autophagy.
- To determine the significance of this pathway in clear-cell renal cell carcinoma (ccRCC) tumorigenesis.
Main Methods:
- Investigated HIF2α interaction with autophagy-lysosome components.
- Assessed HIF2α levels upon autophagy inhibition and induction.
- Utilized genetic and pharmacological approaches to study the interplay between UPS and autophagy in HIF2α degradation.
- Analyzed autophagy gene expression and protein levels in ccRCC patient tumors.
Main Results:
- HIF2α is constitutively degraded, in part, by autophagy.
- HIF2α interacts with autophagy machinery, and its degradation is dependent on the von Hippel-Lindau E3 ligase and p62.
- A compensatory relationship exists between UPS and autophagy in HIF2α degradation.
- Loss or mutation of autophagy genes (e.g., ATG7) and reduced expression of autophagy proteins (ATG7, beclin 1) are associated with ccRCC, correlating with tumor progression.
Conclusions:
- Autophagy plays an anticancer role in ccRCC by degrading HIF2α.
- Constitutive autophagic degradation of HIF2α represents a novel tumor suppression mechanism.
- Dysregulation of autophagy contributes to ccRCC development and progression.
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