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:

The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis

Oncogene volume 40, pages 5482–5494 (2021)Cite this article

Subjects

Abstract

K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-rasG12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: USP16 induction contributes to K-rasG12D-driven lung tumorigenesis in mice.
Fig. 2: USP16 deficiency impairs tumorigencity of K-RAS-activated cells.
Fig. 3: USP16 regulates ROS generation and inhibits cell apoptosis via its deubiquitinase activity.
Fig. 4: p38 activation underlies USP16 deficiency-mediated inhibition of tumor growth.
Fig. 5: USP16 interacts with and deubiquitinates JAK1.
Fig. 6: USP16 coordinates JAK1 and p38 signaling in tumor cells.

Similar content being viewed by others

Code availability

RNAseq data from NCI-H23 and MEF cells, generated in this study, have been uploaded to the NCBI gene expression omnibus (GEO) with the accession code GSE160388 and GSE160485, respectively.

References

  1. Ali SA, Justilien V, Jamieson L, Murray NR, Fields AP. Protein kinase ciota drives a NOTCH3-dependent stem-like phenotype in mutant KRAS lung adenocarcinoma. Cancer Cell. 2016;29:367–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gwinn DM, Lee AG, Briones-Martin-Del-Campo M, Conn CS, Simpson DR, Scott AI, et al. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell. 2018;33:91–107 e106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90.

    Article  CAS  PubMed  Google Scholar 

  4. Kennedy NJ, Cellurale C, Davis RJ. A radical role for p38 MAPK in tumor initiation. Cancer Cell. 2007;11:101–3.

    Article  CAS  PubMed  Google Scholar 

  5. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128:295–308.

    Article  CAS  PubMed  Google Scholar 

  6. Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet. 2004;36:343–50.

    Article  CAS  PubMed  Google Scholar 

  7. Liu D, Huang Y, Zhang L, Liang DN, Li L. Activation of Janus kinase 1 confers poor prognosis in patients with non-small cell lung cancer. Oncol Lett. 2017;14:3959–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Taverna JA, Hung CN, DeArmond DT, Chen M, Lin CL, Osmulski PA, et al. Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer. Cancer Res. 2020;80:1551–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Metz HE, Kargl J, Busch SE, Kim KH, Kurland BF, Abberbock SR, et al. Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma. Proc Natl Acad Sci USA. 2016;113:8795–8800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Deng L, Meng T, Chen L, Wei W, Wang P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther. 2020;5:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai SY, Babbitt RW, Marchesi VT. A mutant deubiquitinating enzyme (Ubp-M) associates with mitotic chromosomes and blocks cell division. Proc Natl Acad Sci USA. 1999;96:2828–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Joo HY, Zhai L, Yang C, Nie S, Erdjument-Bromage H, Tempst P, et al. Regulation of cell cycle progression and gene expression by H2A deubiquitination. Nature. 2007;449:1068–72.

    Article  CAS  PubMed  Google Scholar 

  13. Yang W, Lee YH, Jones AE, Woolnough JL, Zhou D, Dai Q, et al. The histone H2A deubiquitinase Usp16 regulates embryonic stem cell gene expression and lineage commitment. Nat Commun. 2014;5:3818.

    Article  CAS  PubMed  Google Scholar 

  14. Gu Y, Jones AE, Yang W, Liu S, Dai Q, Liu Y, et al. The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function. Proc Natl Acad Sci USA. 2016;113:E51–60.

    Article  CAS  PubMed  Google Scholar 

  15. Xu Y, Yang H, Joo HY, Yu JH, Smith ADT, Schneider D, et al. Ubp-M serine 552 phosphorylation by cyclin-dependent kinase 1 regulates cell cycle progression. Cell cycle. 2013;12:3219–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhuo X, Guo X, Zhang X, Jing G, Wang Y, Chen Q, et al. Usp16 regulates kinetochore localization of Plk1 to promote proper chromosome alignment in mitosis. J cell Biol. 2015;210:727–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang Y, Liu RB, Cao Q, Fan KQ, Huang LJ, Yu JS, et al. USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance. J Clin Investig. 2019;129:2856–71.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Adorno M, Sikandar S, Mitra SS, Kuo A, Nicolis Di Robilant B, Haro-Acosta V, et al. Usp16 contributes to somatic stem-cell defects in Down’s syndrome. Nature. 2013;501:380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001;15:3243–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 2006;8:1775–89.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang J, Zhang P, Wei Y, Piao HL, Wang W, Maddika S, et al. Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol. 2013;15:1486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pan J, Deng Q, Jiang C, Wang X, Niu T, Li H, et al. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene. 2015;34:3957–67.

    Article  CAS  PubMed  Google Scholar 

  23. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adachi Y, Shibai Y, Mitsushita J, Shang WH, Hirose K, Kamata T. Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6. Oncogene. 2008;27:4921–32.

    Article  CAS  PubMed  Google Scholar 

  25. Lim JKM, Leprivier G. The impact of oncogenic RAS on redox balance and implications for cancer development. Cell Death Dis. 2019;10:955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014;6:221ra215.

    Article  CAS  Google Scholar 

  27. Chen X, Shi H, Bi X, Li Y, Huang Z. Targeting the deubiquitinase STAMBPL1 triggers apoptosis in prostate cancer cells by promoting XIAP degradation. Cancer Lett. 2019;456:49–58.

    Article  CAS  PubMed  Google Scholar 

  28. Miotto B, Marchal C, Adelmant G, Guinot N, Xie P, Marto JA, et al. Stabilization of the methyl-CpG binding protein ZBTB38 by the deubiquitinase USP9X limits the occurrence and toxicity of oxidative stress in human cells. Nucleic Acids Res. 2018;46:4392–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nicke B, Bastien J, Khanna SJ, Warne PH, Cowling V, Cook SJ, et al. Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells. Mol cell. 2005;20:673–85.

    Article  CAS  PubMed  Google Scholar 

  30. Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR. p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell. 2007;11:191–205.

    Article  CAS  PubMed  Google Scholar 

  31. Brancho D, Tanaka N, Jaeschke A, Ventura JJ, Kelkar N, Tanaka Y, et al. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 2003;17:1969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ventura JJ, Tenbaum S, Perdiguero E, Huth M, Guerra C, Barbacid M, et al. p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet. 2007;39:750–8.

    Article  CAS  PubMed  Google Scholar 

  33. Qi X, Tang J, Pramanik R, Schultz RM, Shirasawa S, Sasazuki T, et al. p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor. J Biol Chem. 2004;279:22138–44.

    Article  CAS  PubMed  Google Scholar 

  34. Hill KS, Erdogan E, Khoor A, Walsh MP, Leitges M, Murray NR, et al. Protein kinase calpha suppresses Kras-mediated lung tumor formation through activation of a p38 MAPK-TGFbeta signaling axis. Oncogene. 2014;33:2134–44.

    Article  CAS  PubMed  Google Scholar 

  35. Deng K, Liu L, Tan X, Zhang Z, Li J, Ou Y, et al. WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC. Signal Transduct Target Ther. 2020;5:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chuang CH, Greenside PG, Rogers ZN, Brady JJ, Yang D, Ma RK, et al. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med. 2017;23:291–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Song L, Rawal B, Nemeth JA, Haura EB. JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol Cancer Ther. 2011;10:481–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yan M, Sun L, Li J, Yu H, Lin H, Yu T, et al. RNA-binding protein KHSRP promotes tumor growth and metastasis in non-small cell lung cancer. J Exp Clin cancer Res. 2019;38:478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu C, Li X, Hao Y, Wang F, Cheng Z, Geng H, et al. STAT1-induced upregulation of lncRNA KTN1-AS1 predicts poor prognosis and facilitates non-small cell lung cancer progression via miR-23b/DEPDC1 axis. Aging. 2020;12:8680–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang J, Wang F, Liu F, Xu G. Predicting STAT1 as a prognostic marker in patients with solid cancer. Therapeutic Adv Med Oncol. 2020;12:1758835920917558.

    CAS  Google Scholar 

  41. Brooks GD, McLeod L, Alhayyani S, Miller A, Russell PA, Ferlin W, et al. IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. Cancer Res. 2016;76:866–76.

    Article  CAS  PubMed  Google Scholar 

  42. Zhu Z, Aref AR, Cohoon TJ, Barbie TU, Imamura Y, Yang S, et al. Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 2014;4:452–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Grabner B, Schramek D, Mueller KM, Moll HP, Svinka J, Hoffmann T, et al. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat Commun. 2015;6:6285.

    Article  CAS  PubMed  Google Scholar 

  44. D’Amico S, Shi J, Martin BL, Crawford HC, Petrenko O, Reich NC. STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis. Genes Dev. 2018;32:1175–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Zhou J, Qu Z, Yan S, Sun F, Whitsett JA, Shapiro SD, et al. Differential roles of STAT3 in the initiation and growth of lung cancer. Oncogene. 2015;34:3804–14.

    Article  CAS  PubMed  Google Scholar 

  46. Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014;26:207–21.

    Article  CAS  PubMed  Google Scholar 

  47. Lu L, Dong J, Wang L, Xia Q, Zhang D, Kim H, et al. Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide. Oncogene. 2018;37:5292–304.

    Article  CAS  PubMed  Google Scholar 

  48. Obana M, Miyamoto K, Murasawa S, Iwakura T, Hayama A, Yamashita T, et al. Therapeutic administration of IL-11 exhibits the postconditioning effects against ischemia-reperfusion injury via STAT3 in the heart. Am J Physiol Heart Circulatory Physiol. 2012;303:H569–577.

    Article  CAS  Google Scholar 

  49. Fasbender A, Lee JH, Walters RW, Moninger TO, Zabner J, Welsh MJ. Incorporation of adenovirus in calcium phosphate precipitates enhances gene transfer to airway epithelia in vitro and in vivo. J Clin Investig. 1998;102:184–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xu J. Preparation, culture, and immortalization of mouse embryonic fibroblasts. Curr Protoc Mol Biol. 2005; Chapter 28: Unit 28.1.

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81802746, 81572694, and 81972579), and the Natural Science Foundation of Shanghai (20ZR1454100).

Author information

Author notes

  1. These authors contributed equally: Guiqin Xu, Zhaojuan Yang, Yizong Ding.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Guiqin Xu, Zhaojuan Yang, Yun Liu, Li Zhang, Boshi Wang, Ming Tang, Tiantian Jing, Zehong Chen, Lvzhu Xiang, Chen Xu & Yongzhong Liu

  2. Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yizong Ding, Yujie Fu & Xiaojing Zhao

  3. Shanghai Jiao Tong University School of Biomedical Engineering, Shanghai, China

    Kun Jiao & Xiaoli Xu

  4. Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, People’s Republic of China

    Weilin Jin

Authors
  1. Guiqin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhaojuan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yizong Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Boshi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ming Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tiantian Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kun Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoli Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zehong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lvzhu Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yujie Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiaojing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Weilin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yongzhong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.X. and Y.Z.L. defined the project and designed the experiments. G.X. and Z.Y. carried out most of the experiments and analyzed data. Y.D., Y.L., L.Z., M.T., T.J., K.J., X.X., Z.C., L.X., and C.X. participated in experiment conduction. G.X. and B.W. performed bioinformatics analysis. Y.D., Y.F., X.Z., and W.J. provided with technical or material supports. G.X. and Y.Z.L. wrote and edited the paper.

Corresponding author

Correspondence to Yongzhong Liu.

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

Xu, G., Yang, Z., Ding, Y. et al. The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis. Oncogene 40, 5482–5494 (2021). https://doi.org/10.1038/s41388-021-01964-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01964-6

This article is cited by

Search

Advanced search

Quick links