Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis

X. D. Liu, J. Yao, D. N. Tripathi, Z. Ding, Y. Xu, M. Sun, J. Zhang, S. Bai, P. German, A. Hoang, L. Zhou, D. Jonasch, X. Zhang, C. J. Conti, E. Efstathiou, N. M. Tannir, N. T. Eissa, Gordon Mills, C. L. Walker, E. Jonasch

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2450-2460
Number of pages11
JournalOncogene
Volume34
Issue number19
DOIs
StatePublished - May 7 2015
Externally publishedYes

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Autophagy
Carcinogenesis
Kidney
Renal Cell Carcinoma
Proteasome Endopeptidase Complex
Ubiquitin
endothelial PAS domain-containing protein 1
Neoplasms
Ubiquitin-Protein Ligases
Lysosomes
Organelles
Genes
Transcription Factors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Liu, X. D., Yao, J., Tripathi, D. N., Ding, Z., Xu, Y., Sun, M., ... Jonasch, E. (2015). Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. Oncogene, 34(19), 2450-2460. https://doi.org/10.1038/onc.2014.199

Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. / 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, Gordon; Walker, C. L.; Jonasch, E.

In: Oncogene, Vol. 34, No. 19, 07.05.2015, p. 2450-2460.

Research output: Contribution to journalArticle

Liu, XD, Yao, J, Tripathi, DN, Ding, Z, Xu, Y, Sun, M, Zhang, J, Bai, S, German, P, Hoang, A, Zhou, L, Jonasch, D, Zhang, X, Conti, CJ, Efstathiou, E, Tannir, NM, Eissa, NT, Mills, G, Walker, CL & Jonasch, E 2015, 'Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis', Oncogene, vol. 34, no. 19, pp. 2450-2460. https://doi.org/10.1038/onc.2014.199
Liu XD, Yao J, Tripathi DN, Ding Z, Xu Y, Sun M et al. Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. Oncogene. 2015 May 7;34(19):2450-2460. https://doi.org/10.1038/onc.2014.199
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, Gordon ; Walker, C. L. ; Jonasch, E. / Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. In: Oncogene. 2015 ; Vol. 34, No. 19. pp. 2450-2460.
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