title: Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis.
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.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: X-D
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Tripathi
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sun
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bai
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: German
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Hoang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Jonasch
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Houston, TX, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Conti
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: N T
authors.initials: NT
authors.lastname: Eissa
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Walker
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Jonasch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D000071193:Autophagy-Related Protein 7; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D000071186:Beclin-1; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071193:Autophagy-Related Protein 7; D051792:Basic Helix-Loop-Helix Proteins; D000071186:Beclin-1; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D044764:Ubiquitin-Activating Enzymes; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C491997:BECN1 protein, human; C099718:SQSTM1 protein, human; C509349:ATG7 protein, human