Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

TRANSCRIPTIONAL CONTROL AND SIGNAL TRANSDUCTION, CELL CYCLE

MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases

Leukemia volume 36, pages 1150–1159 (2022)Cite this article

Subjects

Abstract

Mitochondria can function as signaling organelles, and part of this output leads to epigenetic remodeling. The full extent of this far-reaching interplay remains undefined. Here, we show that MYC transcriptionally activates IDH2 and increases alpha-ketoglutarate (αKG) levels. This regulatory step induces the activity of αKG-dependent DNA hydroxylases and RNA demethylases, thus reducing global DNA and RNA methylation. MYC, in a IDH2-dependent manner, also promotes the nuclear accumulation of TET1-TET2-TET3, FTO and ALKBH5. Notably, this subcellular movement correlated with the ability of MYC, in an IDH2-dependent manner, and, unexpectedly, of αKG to directly induce O-GlcNAcylation. Concordantly, modulation of the activity of OGT and OGA, enzymes that control the cycling of this non-canonical mono-glycosylation, largely recapitulated the effects of the MYC-IDH2-αKG axis on the subcellular movement of DNA and RNA demethylases. Together, we uncovered a hitherto unsuspected crosstalk between MYC, αKG and O-GlcNAcylation which could influence the epigenome and epitranscriptome homeostasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: IDH2 is a transcriptional target of MYC.
Fig. 2: MYC-IDH2-αKG axis, DNA/RNA methylation and demethylase activity.
Fig. 3: Intermediate metabolites modulate MYC-IDH2 effects on DNA and RNA methylation.
Fig. 4: Control of the subcellular localization of TET1-3, FTO and ALKBH5 by the MYC-IDH2 and MYC-D2HGDH/L2HGDH interplays.
Fig. 5: O-GlcNAcylation and the modulation of TET enzymes and RNA demethylases FTO and ALKBH5.

Similar content being viewed by others

References

  1. Legendre F, MacLean A, Appanna VP, Appanna VD. Biochemical pathways to alpha-ketoglutarate, a multi-faceted metabolite. World J Microbiol Biotechnol. 2020;36:123.

    Article  CAS  PubMed  Google Scholar 

  2. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2:e1600200.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lin AP, Abbas S, Kim SW, Ortega M, Bouamar H, Escobedo Y, et al. D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat Commun. 2015;6:7768.

    Article  CAS  PubMed  Google Scholar 

  4. Ye D, Guan KL, Xiong Y. Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends cancer. 2018;4:151–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Qiu Z, Lin AP, Jiang S, Elkashef SM, Myers J, Srikantan S, et al. MYC regulation of D2HGDH and L2HGDH influences the epigenome and epitranscriptome. Cell Chem Biol. 2020;27:538–50 e537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Oldham WM, Clish CB, Yang Y, Loscalzo J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 2015;22:291–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Intlekofer AM, Dematteo RG, Venneti S, Finley LW, Lu C, Judkins AR, et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 2015;22:304–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu S, He L, Yao K. The antioxidative function of alpha-ketoglutarate and its applications. Biomed Res Int. 2018;2018:3408467.

    PubMed  PubMed Central  Google Scholar 

  9. Losman JA, Koivunen P, Kaelin WG Jr. 2-Oxoglutarate-dependent dioxygenases in cancer. Nat Rev Cancer. 2020;20:710–26.

    Article  CAS  PubMed  Google Scholar 

  10. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510:397–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab. 2020;32:447–56 e446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18:5562–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Elkashef SM, Lin AP, Myers J, Sill H, Jiang D, Dahia PLM, et al. IDH mutation, competitive inhibition of FTO, and RNA methylation. Cancer Cell. 2017;31:619–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Abla H, Sollazzo M, Gasparre G, Iommarini L, Porcelli AM. The multifaceted contribution of alpha-ketoglutarate to tumor progression: an opportunity to exploit? Semin Cell Dev Biol. 2020;98:26–33.

    Article  CAS  PubMed  Google Scholar 

  15. Savoia M, Cencioni C, Mori M, Atlante S, Zaccagnini G, Devanna P, et al. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation. Faseb J. 2019;33:4107–23.

    Article  CAS  PubMed  Google Scholar 

  16. Yang X, Du T, Wang X, Zhang Y, Hu W, Du X, et al. IDH1, a CHOP and C/EBPbeta-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis. Cancer Lett. 2015;365:201–10.

    Article  CAS  PubMed  Google Scholar 

  17. Shechter I, Dai P, Huo L, Guan G. IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J Lipid Res. 2003;44:2169–80.

    Article  CAS  PubMed  Google Scholar 

  18. Butler MJ, Aguiar RCT. Biology informs treatment choices in diffuse large B cell lymphoma. Trends Cancer. 2017;3:871–82.

    Article  PubMed  Google Scholar 

  19. Schaub FX, Dhankani V, Berger AC, Trivedi M, Richardson AB, Shaw R, et al. Pan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas. Cell Syst. 2018;6:282–300 e282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol. 2017;18:452–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schuhmacher M, Staege MS, Pajic A, Polack A, Weidle UH, Bornkamm GW, et al. Control of cell growth by c-Myc in the absence of cell division. Curr Biol CB. 1999;9:1255–1258.

    Article  CAS  PubMed  Google Scholar 

  23. Sasi B, Ethiraj P, Myers J, Lin AP, Jiang S, Qiu Z, et al. Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression. Leukemia. 2021;35:1990–2001.

    Article  CAS  PubMed  Google Scholar 

  24. Kim SW, Rai D, McKeller MR, Aguiar RC. Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL. Blood. 2009;113:6153–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Suhasini AN, Wang L, Holder KN, Lin AP, Bhatnagar H, Kim SW, et al. A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma. Leukemia. 2016;30:617–26.

    Article  CAS  PubMed  Google Scholar 

  26. Bouamar H, Jiang D, Wang L, Lin AP, Ortega M, Aguiar RC. MicroRNA 155 control of p53 activity is context dependent and mediated by Aicda and Socs1. Mol Cell Biol. 2015;35:1329–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qiu Z, Holder KN, Lin AP, Myers J, Jiang S, Gorena KM, et al. Generation and characterization of the Emicro-Irf8 mouse model. Cancer Genet. 2020;245:6–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang D, Aguiar RC. MicroRNA-155 controls RB phosphorylation in normal and malignant B lymphocytes via the noncanonical TGF-beta1/SMAD5 signaling module. Blood. 2014;123:86–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ortega M, Bhatnagar H, Lin AP, Wang L, Aster JC, Sill H, et al. A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies. Leukemia. 2015;29:968–76.

    Article  CAS  PubMed  Google Scholar 

  30. Jung I, Aguiar RC. MicroRNA-155 expression and outcome in diffuse large B-cell lymphoma. Br J Haematol. 2009;144:138–40.

    Article  PubMed  Google Scholar 

  31. Chang TC, Zeitels LR, Hwang HW, Chivukula RR, Wentzel EA, Dews M, et al. Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation. Proc Natl Acad Sci USA. 2009;106:3384–3389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Heckl D, Kowalczyk MS, Yudovich D, Belizaire R, Puram RV, McConkey ME, et al. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat Biotechnol. 2014;32:941–946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim SW, Rai D, Aguiar RC. Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma. Clin Cancer Res. 2011;17:6723–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cooney JD, Lin AP, Jiang D, Wang L, Suhasini AN, Myers J, et al. Synergistic targeting of the regulatory and catalytic subunits of PI3Kdelta in mature B-cell malignancies. Clin Cancer Res. 2018;24:1103–13.

    Article  CAS  PubMed  Google Scholar 

  36. Kelly K, Mejia A, Suhasini AN, Lin AP, Kuhn J, Karnad AB, et al. Safety and pharmacodynamics of the PDE4 inhibitor roflumilast in advanced B-cell malignancies. Clin Cancer Res. 2017;23:1186–92.

    Article  CAS  PubMed  Google Scholar 

  37. Bouamar H, Abbas S, Lin AP, Wang L, Jiang D, Holder KN, et al. A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma. Blood. 2013;122:726–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sodi VL, Khaku S, Krutilina R, Schwab LP, Vocadlo DJ, Seagroves TN, et al. mTOR/MYC axis regulates O-GlcNAc transferase expression and O-GlcNAcylation in breast cancer. Mol Cancer Res. 2015;13:923–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chiaradonna F, Ricciardiello F, Palorini R. The nutrient-sensing hexosamine biosynthetic pathway as the hub of cancer metabolic rewiring. Cells. 2018;7:1–29.

    Article  Google Scholar 

  40. Kim J, Lee HM, Cai F, Ko B, Yang C, Lieu EL, et al. The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer. Nat Metab. 2020;2:1401–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nagel AK, Ball LE. O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity. Amino Acids. 2014;46:2305–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ong Q, Han W, Yang X. O-GlcNAc as an integrator of signaling pathways. Front Endocrinol. 2018;9:599.

    Article  Google Scholar 

  43. Goetzman ES, Prochownik EV. The role for myc in coordinating glycolysis, oxidative phosphorylation, glutaminolysis, and fatty acid metabolism in normal and neoplastic tissues. Front Endocrinol. 2018;9:129.

    Article  Google Scholar 

  44. Hsieh AL, Walton ZE, Altman BJ, Stine ZE, Dang CV. MYC and metabolism on the path to cancer. Semin Cell Dev Biol. 2015;43:11–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chakrabarty RP, Chandel NS. Mitochondria as signaling organelles control mammalian stem cell fate. Cell Stem Cell. 2021;28:394–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Santos JH. Mitochondria signaling to the epigenome: a novel role for an old organelle. Free Radic Biol Med. 2021;170:59–69.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang Q, Liu X, Gao W, Li P, Hou J, Li J, et al. Differential regulation of the ten-eleven translocation (TET) family of dioxygenases by O-linked beta-N-acetylglucosamine transferase (OGT). J Biol Chem. 2014;289:5986–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, Cuomo A, et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell. 2013;49:645–56.

    Article  CAS  PubMed  Google Scholar 

  49. Chen Q, Chen Y, Bian C, Fujiki R, Yu X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature. 2013;493:561–564.

    Article  CAS  PubMed  Google Scholar 

  50. Deplus R, Delatte B, Schwinn MK, Defrance M, Mendez J, Murphy N, et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 2013;32:645–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Huang Y, Rao A. Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet: TIG. 2014;30:464–74.

    Article  CAS  PubMed  Google Scholar 

  52. Ramakrishnan P, Clark PM, Mason DE, Peters EC, Hsieh-Wilson LC, Baltimore D. Activation of the transcriptional function of the NF-kappaB protein c-Rel by O-GlcNAc glycosylation. Sci Signal. 2013;6:ra75.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Golks A, Tran TT, Goetschy JF, Guerini D. Requirement for O-linked N-acetylglucosaminyltransferase in lymphocytes activation. EMBO J. 2007;26:4368–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, et al. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability. Cell Metab. 2012;16:226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Balasubramani A, Rao A. O-GlcNAcylation and 5-methylcytosine oxidation: an unexpected association between OGT and TETs. Mol Cell. 2013;49:618–619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by grants from the National Institute of Health (R01-ES031522 and R01-GM140456), the Cancer Prevention and Research Institute of Texas (CPRIT - RP190043) and the Veterans Administration (I01BX001882), all to RCTA. We thank Jamie Myers for technical help.

Author information

Author notes

  1. These authors contributed equally: An-Ping Lin, Zhijun Qiu.

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA

    An-Ping Lin, Zhijun Qiu, Purushoth Ethiraj, Binu Sasi, Carine Jaafar & Ricardo C. T. Aguiar

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Dinesh Rakheja

  3. South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX, 78229, USA

    Ricardo C. T. Aguiar

Authors
  1. An-Ping Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhijun Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Purushoth Ethiraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Binu Sasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carine Jaafar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dinesh Rakheja
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ricardo C. T. Aguiar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A-PL and ZQ designed, performed, and interpreted the assays; PE, CJ and BS performed experiments; DR performed mass spectrometry measurements of metabolites. RCTA conceived the project, designed, and interpreted the assays, wrote manuscript, which was reviewed by all authors.

Corresponding author

Correspondence to Ricardo C. T. Aguiar.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, AP., Qiu, Z., Ethiraj, P. et al. MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases. Leukemia 36, 1150–1159 (2022). https://doi.org/10.1038/s41375-021-01489-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01489-7

Search

Advanced search

Quick links