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USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression

Oncogene volume 40, pages 6417–6429 (2021)Cite this article

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Abstract

Tumor cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. How these metabolic processes are integrated to fuel cancer cell growth remains largely unknown. Deciphering the regulatory mechanisms is vital to develop targeted strategies for tumor-selective therapies. We herein performed an unbiased and functional siRNA screen against 96 deubiquitinases, which play indispensable roles in cancer and are emerging as therapeutic targets, and identified USP29 as a top candidate essential for metabolic reprogramming that support biosynthesis and survival in tumor cells. Integrated metabolic flux analysis and molecular investigation reveal that USP29 directly deubiquitinates and stabilizes MYC and HIF1α, two master regulators of metabolic reprogramming, enabling adaptive response of tumor cells in both normoxia and hypoxia. Systemic knockout of Usp29 depleted MYC and HIF1α in MYC-driven neuroblastoma and B cell lymphoma, inhibited critical metabolic targets and significantly prolonged survival of tumor-bearing mice. Strikingly, mice homozygous null for the Usp29 gene are viable, fertile, and display no gross phenotypic abnormalities. Altogether, these results demonstrate that USP29 selectively coordinates MYC and HIF1α to integrate metabolic processes critical for cancer cell growth, and therapeutic targeting of USP29, a potentially targetable enzyme, could create a unique vulnerability given deregulation of MYC and HIF1α frequently occurs in human cancers.

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Fig. 1: siRNA screening reveals USP29 as a key regulator of tumor cell metabolic reprogramming.
Fig. 2: USP29 depletion suppresses MYC and HIF1α transcriptional programs.
Fig. 3: USP29 deficiency impairs MYC and HIF1α protein stability.
Fig. 4: USP29 interacts with and deubiquitinates MYC/HIF1α proteins.
Fig. 5: The MYC-JTV1 axis activates USP29 transcription.
Fig. 6: USP29 promotes MYC mediated tumorigenesis.
Fig. 7: A simplified model depicting regulation of metabolic reprogramming by the USP29-MYC/HIF1α axis.

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References

  1. Dang CV. Cancer metabolism: the known, unknowns. Biochim Biophys Acta Rev Cancer. 2018;1870:1.

    Article  CAS  PubMed  Google Scholar 

  2. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37.

    Article  CAS  PubMed  Google Scholar 

  3. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11:85–95.

    Article  CAS  PubMed  Google Scholar 

  4. Pavlova NN, Thompson CB. The Emerging Hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science 2020;368:eaaw5473.

  6. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–70.

    Article  CAS  PubMed  Google Scholar 

  7. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. 2007;178:93–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer. 2013;13:227–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lane AN, Fan TW. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 2015;43:2466–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dong Y, Tu R, Liu H, Qing G. Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Signal Transduct Target Ther. 2020;5:124.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. 2015;5:1024–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008;8:705–13.

    Article  CAS  PubMed  Google Scholar 

  15. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.

    Article  CAS  PubMed  Google Scholar 

  16. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72.

    Article  CAS  PubMed  Google Scholar 

  17. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.

    Article  PubMed  Google Scholar 

  19. Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008;283:28106–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol. 2017;24:1161–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–73.

    Article  CAS  PubMed  Google Scholar 

  22. Cheng J, Guo J, North BJ, Wang B, Cui CP, Li H, et al. Functional analysis of deubiquitylating enzymes in tumorigenesis and development. Biochim Biophys Acta Rev Cancer. 2019;1872:188312.

    Article  CAS  PubMed  Google Scholar 

  23. Harrigan JA, Jacq X, Martin NM, Jackson SP. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2018;17:57–78.

    Article  CAS  PubMed  Google Scholar 

  24. Uchiyama K, Jokitalo E, Kano F, Murata M, Zhang X, Canas B, et al. VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo. J Cell Biol. 2002;159:855–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang Y, Satoh A, Warren G, Meyer HH. VCIP135 acts as a deubiquitinating enzyme during p97-p47-mediated reassembly of mitotic Golgi fragments. J Cell Biol. 2004;164:973–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chandrasekaran AP, Woo SH, Sarodaya N, Rhie BH, Tyagi A, Das S et al. Ubiquitin-specific protease 29 regulates Cdc25A-mediated tumorigenesis. Int J Mol Sci. 2021;22:5766.

  27. Zhang Q, Tang Z, An R, Ye LY, Zhong B. USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity (vol 33, pg 1, 2020). Cell Res. 2020;30:821–2.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kloor M, Bork P, Duwe A, Klaes R, Doeberitz MV, Ridder R. Identification and characterization of UEV3, a human cDNA with similarities to inactive E2 ubiquitin-conjugating enzymes. Biochim Biophys Acta Gene Struct Exp. 2002;1579:219–24.

    Article  CAS  Google Scholar 

  29. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15:110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun RC, Denko NC. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 2014;19:285–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123:3664–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA. 2004;101:9085–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16:2985–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu J, Chung HJ, Vogt M, Jin Y, Malide D, He L, et al. JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. EMBO J. 2011;30:846–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yue M, Jiang J, Gao P, Liu H, Qing G. Oncogenic MYC Activates a feedforward regulatory loop promoting essential amino acid metabolism and tumorigenesis. Cell Rep. 2017;21:3819–32.

    Article  CAS  PubMed  Google Scholar 

  38. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985;318:533–8.

    Article  CAS  PubMed  Google Scholar 

  39. Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.

    Article  CAS  PubMed  Google Scholar 

  40. Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell. 2017;168:657–69.

    Article  PubMed Central  Google Scholar 

  41. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10:671–84.

    Article  Google Scholar 

  42. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3:730–41.

    Article  CAS  PubMed  Google Scholar 

  43. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. New Engl J Med. 2009;360:765–73.

    Article  CAS  PubMed  Google Scholar 

  44. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. New Engl J Med. 2009;361:1058–66.

    Article  CAS  PubMed  Google Scholar 

  45. Zhu J, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 2019;20:436–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.

    Article  CAS  PubMed  Google Scholar 

  47. Dang CV. A time for MYC: metabolism and therapy. Cold Spring Harb Symp Quant Biol. 2016;81:79–83.

    Article  PubMed  Google Scholar 

  48. Su H, Hu J, Huang L, Yang Y, Thenoz M, Kuchmiy A, et al. SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival. Nat Commun. 2018;9:4281.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Yuan M, Breitkopf SB, Yang X, Asara JM. A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat Protoc. 2012;7:872–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jiang J, Wang J, Yue M, Cai X, Wang T, Wu C, et al. Direct phosphorylation and stabilization of MYC by aurora B kinase promote T-cell leukemogenesis. Cancer Cell. 2020;37:200–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all members of the Qing lab for helpful suggestions, the Core Facility of Medical Research Institute at Wuhan University for providing hypoxia workstations and histology platform. We also thank Dr William A. Weiss (University of California, San Francisco) for providing transgenic TH-MYCN mice, Dr Wuhan Xiao (Institute of Hydrobiology, Chinese Academy of Sciences) for providing transgenic Eμ-Myc mice. This study was supported by grants from National Key R&D Program of China (2017YFA0505600 to G.Q.), National Natural Science Foundation of China (81970152, 81770177 to H.L., 81830084 to G.Q.), National Science Foundation for Distinguished Young Scholar (81725013 to G.Q., 82025003 to H.L.).

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  1. These authors contributed equally: Rongfu Tu, Wenqian Kang.

Authors and Affiliations

  1. Department of Urology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China

    Rongfu Tu, Wenqian Kang & Guoliang Qing

  2. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, 430071, Wuhan, China

    Rongfu Tu, Wenqian Kang, Mengjie Yang, Liyuan Wang, Qing Bao, Zhi Chen, Yang Dong, Jingchao Wang, Jue Jiang, Hudan Liu & Guoliang Qing

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Contributions

G.Q. and R.T. conceived and designed the study. G.Q. and H.L. supervised the study. H.L., G.Q., R.T., and W.K. wrote the manuscript. R.T. and W.K. performed most of the experiments. M.Y., L.W., and Y.D. provided technical assistance for mice experiments. Q.B. conducted molecular cloning experiments. Z.C. provided technical assistance for hypoxic experiments. J.W. and J.J carried out ChIP experiments and cell culture. All authors read and approved the final paper.

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Correspondence to Guoliang Qing.

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All animal experiments were performed following the university laboratory animal guidelines and approved by the Animal Experimentations Ethics Committee of Wuhan University School of Medicine.

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Tu, R., Kang, W., Yang, M. et al. USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression. Oncogene 40, 6417–6429 (2021). https://doi.org/10.1038/s41388-021-02031-w

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