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Aberrant JmjC domain-containing protein 8 (JMJD8) expression promotes activation of AKT and tumor epithelial–mesenchymal transition

Oncogene volume 39, pages 6451–6467 (2020)Cite this article

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A Correction to this article was published on 26 March 2021

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Abstract

Posttranslational modifications of histone and nonhistone proteins greatly influence numerous molecular events in multiple diseases. Jumonji domain-containing proteins are a family functioning as histone demethylase. Jumonji domain-containing protein 8 (JMJD8) is Jumonji C (JmjC) domain-only member of this family, and its physiological functions remain largely unknown. In this study, we investigated the mechanism by which aberrant JMJD8 stimulates phosphorylation of AKT and activate AKT/GSK3β/β-catenin signaling pathway thereby promotes tumor cell epithelial–mesenchymal transition (EMT). We demonstrated that knockdown of JMJD8 increased the interaction of SETDB1 and phosphoinositide-dependent kinase 1 (PDK1) with AKT1 and resulted in enhanced trimethylation of AKT1 at lysine 142 (K142), which is crucial for cell membrane recruitment, phosphorylation, and activation of AKT. Moreover, the mutation of histidine 200 of JMJD8 (JMJD8-H200Q) disrupted its binding with AKT1 and increased interaction of SETDB1 and PDK1 with AKT1. Furthermore, histone demethylase jumonji domain-containing protein 2B functioned as an adapter to recruit β-catenin to the methylated AKT1 upon JMJD8 depression, which facilitated the phosphorylation of β-catenin at Ser552 and its accumulation in cell nucleus where the activated β-catenin transcriptionally stimulated the expression of genes involved in EMT. In conclusion, our data unraveled a novel role of JMJD8 in regulating the migration and invasion of tumor via modulating AKT methylation and activation. In addition, this study showed that JMJD8 is a potential biomarker and drug design target for tumor EMT.

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Fig. 1: JMJD8 regulates tumor cells proliferation, migration, and invasion.
Fig. 2: JMJD8 knockdown leads to accumulation of β-catenin.
Fig. 3: AKT is required for JMJD8-mediated EMT.
Fig. 4: JMJD8 regulates membrane localization of AKT1.
Fig. 5: JMJD8 interacts with AKT1.
Fig. 6: JMJD8 suppresses SETDB1-mediated methylation of AKT1.
Fig. 7: JMJD8-regulated AKT1-K142 methylation is critical for AKT activation.
Fig. 8: JMJD2B promotes AKT-mediated β-catenin phosphorylation under JMJD8 depression.

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References

  1. Suva ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013;339:1567–70.

    Article  CAS  PubMed  Google Scholar 

  2. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    Article  CAS  PubMed  Google Scholar 

  4. Kelly AD, Issa JJ. The promise of epigenetic therapy: reprogramming the cancer epigenome. Curr Opin Genet Dev. 2017;42:68–77.

    Article  CAS  PubMed  Google Scholar 

  5. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8:286–98.

    Article  CAS  PubMed  Google Scholar 

  6. Revathidevi S, Munirajan AK. Akt in cancer: mediator and more. Semin Cancer Biol. 2019;59:80–91.

    Article  CAS  PubMed  Google Scholar 

  7. De Santis MC, Gulluni F, Campa CC, Martini M, Hirsch E. Targeting PI3K signaling in cancer: challenges and advances. Biochim Biophys Acta Rev Cancer. 2019;1871:361–6.

    Article  PubMed  CAS  Google Scholar 

  8. Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta. 2011;1813:1938–45.

    Article  CAS  PubMed  Google Scholar 

  9. Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul. 2017;65:5–15.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell. 2006;24:185–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Song Y, Li ZX, Liu X, Wang R, Li LW, Zhang Q. The Wnt/beta-catenin and PI3K/Akt signaling pathways promote EMT in gastric cancer by epigenetic regulation via H3 lysine 27 acetylation. Tumour Biol. 2017;39:1010428317712617.

    PubMed  Google Scholar 

  12. Jamieson C, Sharma M, Henderson BR. Wnt signaling from membrane to nucleus: beta-catenin caught in a loop. Int J Biochem Cell Biol. 2012;44:847–50.

    Article  CAS  PubMed  Google Scholar 

  13. Zhao L, Li W, Zang W, Liu Z, Xu X, Yu H, et al. JMJD2B promotes epithelial-mesenchymal transition by cooperating with beta-catenin and enhances gastric cancer metastasis. Clin Cancer Res. 2013;19:6419–29.

    Article  CAS  PubMed  Google Scholar 

  14. Yang F, Xu J, Li H, Tan M, Xiong X, Sun Y. FBXW2 suppresses migration and invasion of lung cancer cells via promoting beta-catenin ubiquitylation and degradation. Nat Commun. 2019;10:1382.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Yeo KS, Tan MC, Lim YY, Ea CK. JMJD8 is a novel endoplasmic reticulum protein with a JmjC domain. Sci Rep. 2017;7:15407.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Boeckel JN, Derlet A, Glaser SF, Luczak A, Lucas T, Heumuller AW, et al. JMJD8 regulates angiogenic sprouting and cellular metabolism by interacting with pyruvate kinase M2 in endothelial cells. Arterioscl Throm Vas. 2016;36(7):1425–33.

    Article  CAS  Google Scholar 

  17. Yang Q, Jiang W, Hou P. Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Semin Cancer Biol. 2019;59:112–24.

    Article  CAS  PubMed  Google Scholar 

  18. Guo J, Dai X, Laurent B, Zheng N, Gan W, Zhang J, et al. AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions. Nat Cell Biol. 2019;21:226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang G, Long J, Gao Y, Zhang W, Han F, Xu C, et al. SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis. Nat Cell Biol. 2019;21:214–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Su Y, Wang J. JmjC domain-containing protein 8 (JMJD8) represses Ku70/Ku80 expression via attenuating AKT/NF-kappaB/COX-2 signaling. Biochim Biophys Acta Mol Cell Res. 2019;1866:118541.

    Article  CAS  PubMed  Google Scholar 

  21. Henderson V, Smith B, Burton LJ, Randle D, Morris M, Odero-Marah VA. Snail promotes cell migration through PI3K/AKT-dependent Rac1 activation as well as PI3K/AKT-independent pathways during prostate cancer progression. Cell Adh Migr. 2015;9:255–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li Q, Hou L, Ding G, Li Y, Wang J, Qian B, et al. KDM6B induces epithelial-mesenchymal transition and enhances clear cell renal cell carcinoma metastasis through the activation of SLUG. Int J Clin Exp Pathol. 2015;8:6334–44.

    PubMed  PubMed Central  Google Scholar 

  23. Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, et al. Aberrant JMJD3 expression upregulates slug to promote migration, invasion, and stem cell-like behaviors in hepatocellular carcinoma. Cancer Res. 2016;76:6520–32.

    Article  CAS  PubMed  Google Scholar 

  24. Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, et al. JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells. Oncotarget. 2015;6:12723–39.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ghahhari NM, Babashah S. Interplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer. Eur J Cancer. 2015;51:1638–49.

    Article  CAS  PubMed  Google Scholar 

  26. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gao C, Xiao G, Hu J. Regulation of Wnt/beta-catenin signaling by posttranslational modifications. Cell Biosci. 2014;4:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837–47.

    Article  CAS  PubMed  Google Scholar 

  29. Hino S, Tanji C, Nakayama KI, Kikuchi A. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol. 2005;25:9063–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fang DX, Hawke D, Zheng YH, Xia Y, Meisenhelder J, Nika H, et al. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007;282:11221–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kohn AD, Takeuchi F, Roth RA. Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem. 1996;271:21920–6.

    Article  CAS  PubMed  Google Scholar 

  32. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.

    Article  CAS  PubMed  Google Scholar 

  33. Hamamoto R, Saloura V, Nakamura Y. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat Rev Cancer. 2015;15:110–24.

    Article  CAS  PubMed  Google Scholar 

  34. Guo J, Wei W. Fine-tuning AKT kinase activity through direct lysine methylation. Cell Cycle. 2019;18:917–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 2016;67:11–28.

    Article  CAS  PubMed  Google Scholar 

  36. Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016;166:21–45.

    Article  CAS  PubMed  Google Scholar 

  37. Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G. Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet. 2017;33:943–59.

    Article  CAS  PubMed  Google Scholar 

  38. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016;15:18.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sun L, Fang J. Epigenetic regulation of epithelial-mesenchymal transition. Cell Mol Life Sci. 2016;73:4493–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sechler M, Parrish JK, Birks DK, Jedlicka P. The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene. 2017;36:4150–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yeo KS, Tan MC, Wong WY, Loh SW, Lam YL, Tan CL, et al. JMJD8 is a positive regulator of TNF-induced NF-kappaB signaling. Sci Rep. 2016;6:34125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alam H, Gu B, Lee MG. Histone methylation modifiers in cellular signaling pathways. Cell Mol Life Sci. 2015;72:4577–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang J, Jing L, Li M, He L, Guo Z. Regulation of histone arginine methylation/demethylation by methylase and demethylase (review). Mol Med Rep. 2019;19:3963–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Oh S, Shin S, Janknecht R. The small members of the JMJD protein family: enzymatic jewels or jinxes? Biochim Biophys Acta Rev Cancer. 2019;1871:406–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chu N, Salguero AL, Liu AZ, Chen Z, Dempsey DR, Ficarro SB, et al. Akt kinase activation mechanisms revealed using protein semisynthesis. Cell. 2018;174:897–907.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shin S, Janknecht R. Diversity within the JMJD2 histone demethylase family. Biochem Bioph Res Commun. 2007;353:973–7.

    Article  CAS  Google Scholar 

  47. Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen ZZ, et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006;125:467–81.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation (11575232, 31471268), the National Key Research and Development Program of China (Stem Cell and Translational Research) 2016YFA0101202, the International Partnership Program of Chinese Academy of Sciences (116134KYSB20160084), and the Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (2016FXCX005).

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  1. These authors contributed equally: Yao Su, Xueying Wang

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  1. Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, HFIPS, Chinese Academy of Sciences, Hefei, 230031, PR China

    Yao Su & Jun Wang

  2. Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China

    Xueying Wang & Zhen Guo

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Su, Y., Wang, X., Guo, Z. et al. Aberrant JmjC domain-containing protein 8 (JMJD8) expression promotes activation of AKT and tumor epithelial–mesenchymal transition. Oncogene 39, 6451–6467 (2020). https://doi.org/10.1038/s41388-020-01446-1

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