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:

Ubiquitin specific peptidase 38 epigenetically regulates KLF transcription factor 5 to augment malignant progression of lung adenocarcinoma

Oncogene volume 43, pages 1190–1202 (2024)Cite this article

Subjects

Abstract

Protein ubiquitination is a common post-translational modification and a critical mechanism for regulating protein stability. This study aimed to explore the role and potential molecular mechanism of ubiquitin-specific peptidase 38 (USP38) in the progression of lung adenocarcinoma (LUAD). USP38 expression was significantly higher in patients with LUAD than in their counterparts, and higher USP38 expression was closely associated with a worse prognosis. USP38 silencing suppresses the proliferation of LUAD cells in vitro and impedes the tumorigenic activity of cells in xenograft mouse models in vivo. Further, we found that USP38 affected the protein stability of transcription factor Krüppel-like factors 5 (KLF5) by inhibiting its degradation. Subsequent mechanistic investigations showed that the N-terminal of USP38 (residues 1-400aa) interacted with residues 1-200aa of KLF5, thereby stabilizing the KLF5 protein by deubiquitination. Moreover, we found that PIAS1-mediated SUMOylation of USP38 was promoted, whereas SENP2-mediated de-SUMOylation of USP38 suppressed the deubiquitination effects of USP38 on KLF5. Additionally, our results demonstrated that KLF5 overexpression restored the suppression of the malignant properties of LUAD cells by USP38 knockdown. SUMOylation of USP38 enhances the deubiquitination and stability of KLF5, thereby augmenting the malignant progression of LUAD.

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: USP38 is highly expressed in LUAD and its high expression correlates with poor prognosis.
Fig. 2: USP38 knockdown inhibits the malignant process of LUAD in vitro and in vivo.
Fig. 3: USP38 interacts with KLF5 and enhances its protein stability.
Fig. 4: USP38 regulates the K-33 and K48-linked ubiquitin chains of KLF5 via its deubiquitination enzyme activity.
Fig. 5: USP38 and KLF5 interact through their respective N-terminal end.
Fig. 6: USP38 SUMOylation enhances its de-ubiquitination activity against KLF5.
Fig. 7: USP38 promotes the growth of LUAD cells in KLF5-dependent manner.

Similar content being viewed by others

Data availability

All relevant data are available from the authors upon request.

References

  1. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.

    Article  CAS  PubMed  Google Scholar 

  2. Erratum: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2020;70:313.

  3. Reck M, Heigener DF, Mok T, Soria J-C, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382:709–19.

    Article  CAS  PubMed  Google Scholar 

  4. Magiera MM, Singh P, Janke C. SnapShot: functions of tubulin posttranslational modifications. Cell. 2018;173:1552–1552.e1.

    Article  CAS  PubMed  Google Scholar 

  5. Hochstrasser M. Origin and function of ubiquitin-like proteins. Nature. 2009;458:422–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gallo LH, Ko J, Donoghue DJ. The importance of regulatory ubiquitination in cancer and metastasis. Cell Cycle. 2017;16:634–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou Y-H, et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell. 2015;160:715–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Parvatiyar K, Harhaj EW. Cell signaling. Anchors away for ubiquitin chains. Science. 2010;328:1244–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Komander D, Clague MJ, Urbé S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10:550–63.

    Article  CAS  PubMed  Google Scholar 

  10. Abdul Rehman SA, Kristariyanto YA, Choi S-Y, Nkosi PJ, Weidlich S, Labib K, et al. MINDY-1 Is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes. Mol Cell. 2016;63:146–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nijman SMB, Luna-Vargas MPA, Velds A, Brummelkamp TR, Dirac AMG, Sixma TK, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123:773–86.

    Article  CAS  PubMed  Google Scholar 

  12. Tang J, Luo Y, Xiao L. USP26 promotes anaplastic thyroid cancer progression by stabilizing TAZ. Cell Death Dis. 2022;13:326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith CH, et al. Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol. 2006;13:285–91.

    Article  CAS  PubMed  Google Scholar 

  14. Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y. Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway. PLoS Biol. 2006;4:e27.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tavana O, Li D, Dai C, Lopez G, Banerjee D, Kon N, et al. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med. 2016;22:1180–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu H-T, Kuo Y-C, Hung J-J, Huang C-H, Chen W-Y, Chou T-Y, et al. K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression. Nat Commun. 2016;7:13644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang Q, Ma S, Song N, Li X, Liu L, Yang S, et al. Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis. J Clin Investig. 2016;126:2205–20.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yang Y, Yang C, Li T, Yu S, Gan T, Hu J, et al. The deubiquitinase USP38 promotes NHEJ repair through regulation of HDAC1 activity and regulates cancer cell response to genotoxic insults. Cancer Res. 2020;80:719–31.

    Article  CAS  PubMed  Google Scholar 

  19. Chen S, Yun F, Yao Y, Cao M, Zhang Y, Wang J, et al. USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein. J Exp Med. 2018;215:2850–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lin M, Zhao Z, Yang Z, Meng Q, Tan P, Xie W, et al. USP38 inhibits Type I interferon signaling by editing TBK1 ubiquitination through NLRP4 signalosome. Mol Cell. 2016;64:267–81.

    Article  CAS  PubMed  Google Scholar 

  21. Flotho A, Melchior F. Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem. 2013;82:357–85.

    Article  CAS  PubMed  Google Scholar 

  22. Li Y, Varejão N, Reverter D. Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1. Nat Commun. 2022;13:1819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhen Y, Knobel PA, Stracker TH, Reverter D. Regulation of USP28 deubiquitinating activity by SUMO conjugation. J Biol Chem. 2014;289:34838–50.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lopitz-Otsoa F, Delgado TC, Lachiondo-Ortega S, Azkargorta M, Elortza F, Rodríguez MS. et al. SUMO-binding entities (SUBEs) as tools for the enrichment, isolation, identification, and characterization of the SUMO proteome in liver cancer. J Vis Exp. 2019;153:60098.

    Google Scholar 

  25. Yeh ET. SUMOylation and De-SUMOylation: wrestling with life’s processes. J Biol Chem. 2009;284:8223–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Salas-Lloret D, González-Prieto R. Insights in post-translational modifications: ubiquitin and SUMO. Int J Mol Sci. 2022;23:3281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Praefcke GJK, Hofmann K, Dohmen RJ. SUMO playing tag with ubiquitin. Trends Biochem Sci. 2012;37:23–31.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Li Q, Hu D, Gao D, Wang W, Wu K, et al. USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination. Viruses. 2021;13:2029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhan W, Liao X, Liu J, Tian T, Yu L, Li R. USP38 regulates the stemness and chemoresistance of human colorectal cancer via regulation of HDAC3. Oncogenesis. 2020;9:48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zheng Z, Shang Y, Xu R, Yan X, Wang X, Cai J, et al. Ubiquitin specific peptidase 38 promotes the progression of gastric cancer through upregulation of fatty acid synthase. Am J Cancer Res. 2022;12:2686–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lyu Y, Guan Y, Deliu L, Humphrey E, Frontera JK, Yang YJ, et al. KLF5 governs sphingolipid metabolism and barrier function of the skin. Genes Dev. 2022;36:822–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li X, Liu X, Xu Y, Liu J, Xie M, Ni W, et al. KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α. Int J Oncol. 2014;45:1507–14.

    Article  CAS  PubMed  Google Scholar 

  33. Zhao C, Li Y, Qiu W, He F, Zhang W, Zhao D, et al. C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation. Oncogene. 2018;37:4821–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shi J, Yang C, An J, Hao D, Liu C, Liu J, et al. KLF5-induced BBOX1-AS1 contributes to cell malignant phenotypes in non-small cell lung cancer via sponging miR-27a-5p to up-regulate MELK and activate FAK signaling pathway. J Exp Clin Cancer Res. 2021;40:148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang T, Wang B, Su F, Gu B, Xiang L, Gao L, et al. TCF7L2 promotes anoikis resistance and metastasis of gastric cancer by transcriptionally activating PLAUR. Int J Biol Sci. 2022;18:4560–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by funding from National Natural Science Foundation of China (81802269 and 82260518); Medical Innovation and Development Project of Lanzhou University (lzuyxcx-2022-183); Construction Project of Clinical Medical Research Center from Gansu Provincial Department of Science and Technology (21JR7RA390); Key Research and Development Plan from Gansu Provincial Department of Science and Technology (22YF7FA086); Unite Pesearch Foundation of Gansu Province (23JRRA1497); Natural Science Foundation of Gansu Province (20JR5RA352 and 22JR5RA918); Youth Science and Technology Talent Innovation Project of Lanzhou City (2023-QN-14); Scientific and Technological Development Guiding Plan Project of Lanzhou City (2020-ZD-74).

Author information

Author notes

  1. These authors contributed equally: Tao Zhang, Fei Su, Bofang Wang, Lixin Liu.

Authors and Affiliations

  1. Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China

    Tao Zhang, Fei Su, Yongbin Lu, Huanyu Dai, Tianning Yang, Jingru Yang, Rui Chen, Da Zhao & Xiaoming Hou

  2. The second clinical medical college of Lanzhou University, Lanzhou, Gansu, PR China

    Bofang Wang

  3. Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China

    Lixin Liu, Ruijiang Ling & Peng Yue

  4. Department of Radiotherapy, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China

    Hongxin Su

  5. The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, PR China

    Ruiyue Wu & Kaili Zhu

Authors
  1. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fei Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bofang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lixin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yongbin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongxin Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruijiang Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peng Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huanyu Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tianning Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jingru Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ruiyue Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kaili Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Da Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xiaoming Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T. Zhang: Data curation, formal analysis, validation, visualization, methodology, writing–original draft, writing–review and editing. F. Su: Formal analysis, validation, visualization, methodology. B. Wang: Data curation, software, formal analysis, visualization, methodology. Y. Lu: Methodology. H. Su: Data curation, formal analysis. R. Ling: Methodology. P. Yue: Methodology. H. Dai: Methodology. T. Yang: Methodology. J. Yang: Funding acquisition, methodology. R. Chen: Methodology. R. Wu: Methodology. K. Zhu: Methodology. R. Chen: Conceptualization, supervision, project administration. D. Zhao: Conceptualization, supervision, funding acquisition, writing–original draft, project administration, writing–review and editing. X. Hou: Conceptualization, supervision, funding acquisition, writing–original draft, project administration, writing– review and editing.

Corresponding authors

Correspondence to Fei Su, Da Zhao or Xiaoming Hou.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, T., Su, F., Wang, B. et al. Ubiquitin specific peptidase 38 epigenetically regulates KLF transcription factor 5 to augment malignant progression of lung adenocarcinoma. Oncogene 43, 1190–1202 (2024). https://doi.org/10.1038/s41388-024-02985-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-02985-7

Search

Advanced search

Quick links