Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis

Article metrics


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7


  1. 1

    Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J et al. State of the science: an update on renal cell carcinoma. Mol Cancer Res 2012; 10: 859–880.

  2. 2

    Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14: 4726–4734.

  3. 3

    Keith B, Johnson RS, Simon MC . HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 2012; 12: 9–22.

  4. 4

    Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S et al. Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov 2011; 1: 222–235.

  5. 5

    Shinojima T, Oya M, Takayanagi A, Mizuno R, Shimizu N, Murai M . Renal cancer cells lacking hypoxia inducible factor (HIF)-1alpha expression maintain vascular endothelial growth factor expression through HIF-2alpha. Carcinogenesis 2007; 28: 529–536.

  6. 6

    Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC . HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 2007; 11: 335–347.

  7. 7

    Vanharanta S, Shu W, Brenet F, Hakimi AA, Heguy A, Viale A et al. Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat Med 2013; 19: 50–56.

  8. 8

    Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 2012; 44: 17–19.

  9. 9

    Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 2013; 45: 860–867.

  10. 10

    Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499: 43–49.

  11. 11

    He C, Klionsky DJ . Regulation mechanisms and signaling pathways of autophagy. Annual Review of Genetics 2009; 43: 67–93.

  12. 12

    Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT . Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 2007; 27: 135–144.

  13. 13

    Kirkin V, McEwan DG, Novak I, Dikic I . A role for ubiquitin in selective autophagy. Mol Cell 2009; 34: 259–269.

  14. 14

    Moscat J, Diaz-Meco MT . P62 at the crossroads of autophagy, apoptosis, and cancer. Cell 2009; 137: 1001–1004.

  15. 15

    Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 2007; 171: 513–524.

  16. 16

    Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007; 447: 859–863.

  17. 17

    White E . Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012; 12: 401–410.

  18. 18

    Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672–676.

  19. 19

    Yue Z, Jin S, Yang C, Levine AJ, Heintz N . Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100: 15077–15082.

  20. 20

    Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809–1820.

  21. 21

    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–892.

  22. 22

    Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ . A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 2008; 14: 90–102.

  23. 23

    Mizushima N, Yoshimori T, Levine B . Methods in mammalian autophagy research. Cell 2010; 140: 313–326.

  24. 24

    Dai C, Gu W . P53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med 2010; 16: 528–536.

  25. 25

    Yuan Y, Hilliard G, Ferguson T, Millhorn DE . Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem 2003; 278: 15911–15916.

  26. 26

    Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2: 423–427.

  27. 27

    Hacker KE, Lee CM, Rathmell WK . VHL type 2B mutations retain VBC complex form and function. PLoS One 2008; 3: e3801.

  28. 28

    Kim J, Kundu M, Viollet B, Guan KL . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132–141.

  29. 29

    Tripathi DN, Chowdhury R, Trudel LJ, Tee AR, Slack RS, Walker CL et al. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proc Natl Acad Sci USA 2013; 110: E2950–E2957.

  30. 30

    Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 2009; 461: 654–658.

  31. 31

    Urushitani M, Kurisu J, Tsukita K, Takahashi R . Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J Neurochem 2002; 83: 1030–1042.

  32. 32

    Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 2002; 1: 459–468.

  33. 33

    Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B . The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 2010; 11: 329–341.

  34. 34

    Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009; 11: 385–396.

  35. 35

    Murrow L, Debnath J . Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu Rev Pathol 2013; 8: 105–137.

  36. 36

    Prasad SR, Humphrey PA, Catena JR, Narra VR, Srigley JR, Cortez AD et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics 2006; 26: 1795–1806.

  37. 37

    Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT et al. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell 2008; 13: 343–354.

  38. 38

    Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137: 1062–1075.

  39. 39

    Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334: 1573–1577.

  40. 40

    Hubbi ME, Hu H, Kshitiz, Ahmed I, Levchenko A, Semenza GL . Chaperone-mediated autophagy targets hypoxia-inducible factor-1alpha (HIF-1alpha) for lysosomal degradation. J Biol Chem 2013; 288: 10703–10714.

  41. 41

    Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC . Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 2009; 33: 517–527.

  42. 42

    Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 2007; 131: 1149–1163.

  43. 43

    Liu XD, Ko S, Xu Y, Fattah EA, Xiang Q, Jagannath C et al. Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress. J Biol Chem 2012; 287: 19687–19698.

  44. 44

    Ding Z, German P, Bai S, Feng Z, Gao M, Si W et al. Agents that stabilize mutated von Hippel-Lindau (VHL) protein: results of a high-throughput screen to identify compounds that modulate VHL proteostasis. J Biomol Screen 2012; 17: 572–580.

  45. 45

    Kim J, Jonasch E, Alexander A, Short JD, Cai S, Wen S et al. Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res 2009; 15: 81–90.

Download references


We acknowledge the TCGA Research network. This work was supported by the Nanomedicine Roadmap Initiative Grant, the Renee Kaye Cure Fur Cancer Grant and the MD Anderson Cancer Center Kidney Cancer Research Program.

Author information

Correspondence to X-D Liu or E Jonasch.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Yao, J., Tripathi, D. et al. Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. Oncogene 34, 2450–2460 (2015) doi:10.1038/onc.2014.199

Download citation

Further reading