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:

Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin

Oncogene volume 38, pages 7457–7472 (2019)Cite this article

Subjects

Abstract

The E3 ligase S-phase kinase-associated protein 2(Skp2) is overexpressed in human cancers and correlated with poor prognosis, but its contributions to tumorigenesis and chemoresistance in nasopharyngeal carcinoma (NPC) are not evident. Herein we show that Skp2 is highly expressed in NPC tumor tissues and cell lines. Knockdown of Skp2 suppresses tumor cell growth, colony formation, glycolysis, and in vivo tumor growth. Skp2 promotes Akt K63-mediated ubiquitination and activation, which is required for EGF-induced Akt mitochondrial localization. Importantly, K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization. Overexpression of Skp2 impaired the intrinsic apoptotic pathway and confers cisplatin resistance. Moreover, ectopic expression of Myr-Akt1 or phosphomimetic HK2-T473D rescued cisplatin-induced tumor suppression in Skp2 knockdown stable cells. Also, depletion of Akt ubiquitination enhances the antitumor efficacy of cisplatin in vitro and in vivo. Finally, we demonstrated that Skp2 is positively correlated with p-Akt and HK2 in NPC tumor tissues. This study highlights the clinical value of Skp2 targeting in NPC treatment.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, et al. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell. 2012;149:1098–111.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhao H, Bauzon F, Fu H, Lu Z, Cui J, Nakayama K, et al. Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer Cell. 2013;24:645–59.

    CAS  PubMed  Google Scholar 

  3. Lee SW, Li CF, Jin G, Cai Z, Han F, Chan CH, et al. Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell. 2015;57:1022–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Timmerbeul I, Garrett-Engele CM, Kossatz U, Chen X, Firpo E, Grunwald V, et al. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci USA. 2006;103:14009–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Shi C, Pan BQ, Shi F, Xie ZH, Jiang YY, Shang L, et al. Sequestosome 1 protects esophageal squamous carcinoma cells from apoptosis via stabilizing SKP2 under serum starvation condition. Oncogene. 2018;37:3260–74.

    CAS  PubMed  Google Scholar 

  6. Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer. 2008;8:438–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, et al. Skp2 is a promising therapeutic target in breast cancer. Front Oncol. 2012;1:18702.

    PubMed  Google Scholar 

  8. Bhattacharyya T, Babu G, Kainickal CT. Current role of chemotherapy in nonmetastatic nasopharyngeal cancer. J Oncol. 2018;2018:3725837.

    PubMed  PubMed Central  Google Scholar 

  9. Katano A, Takahashi W, Yamashita H, Yamamoto K, Ando M, Yoshida M, et al. Radiotherapy alone and with concurrent chemotherapy for nasopharyngeal carcinoma: A retrospective study. Medicine. 2018;97:e0502.

    PubMed  PubMed Central  Google Scholar 

  10. Lam WKJ, Chan JYK. Recent advances in the management of nasopharyngeal carcinoma. F1000Res. 2018;7:F1000.

    PubMed  PubMed Central  Google Scholar 

  11. Lee VH, Lam KO, Chang AT, Lam TC, Chiang CL, So TH, et al. Management of nasopharyngeal carcinoma: is adjuvant therapy needed? J Oncol Pract. 2018;14:594–602.

    PubMed  Google Scholar 

  12. Shuang H, Feng J, Caineng C, Qifeng J, Tin J, Yuanyuan, et al. The value of radical radiotherapy in the primary tumor of newly diagnosed oligo-metastatic nasopharyngeal carcinoma patients. Clin Transl Oncol. 2018;21:213–9.

    PubMed  Google Scholar 

  13. Wang J, Huang Y, Guan Z, Zhang JL, Su HK, Zhang W, et al. E3-ligase Skp2 predicts poor prognosis and maintains cancer stem cell pool in nasopharyngeal carcinoma. Oncotarget. 2014;5:5591–601.

    PubMed  PubMed Central  Google Scholar 

  14. Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169:381–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Li W, Peng C, Lee MH, Lim D, Zhu F, Fu Y, et al. TRAF4 is a critical molecule for Akt activation in lung cancer. Cancer Res. 2013;73:6938–50.

    CAS  PubMed  Google Scholar 

  16. Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 2009;325:1134–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Li W, Gao F, Ma X, Wang R, Dong X, Wang W. Deguelin inhibits non-small cell lung cancer via down-regulating Hexokinases II-mediated glycolysis. Oncotarget. 2017;8:32586–99.

    PubMed  PubMed Central  Google Scholar 

  18. Roberts DJ, Tan-Sah VP, Smith JM, Miyamoto S. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem. 2013;288:23798–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 2011;11:239–53.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Swatek KN, Komander D. Ubiquitin modifications. Cell Res. 2016;26:399–422.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H. p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol. 1999;9:661–4.

    CAS  PubMed  Google Scholar 

  23. Yu ZK, Gervais JL, Zhang H. Human CUL-1 associates with the SKP1/SKP2 complex and regulatesp21(CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci USA. 1998;95:11324–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wu J, Zhang X, Zhang L, Wu CY, Rezaeian AH, Chan CH, et al. Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1. Mol Cell. 2012;46:351–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yao F, Zhou Z, Kim J, Hang Q, Xiao Z, Ton BN, et al. SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. Nat Commun. 2018;9:2269.

    PubMed  PubMed Central  Google Scholar 

  26. Byun WS, Jin M, Yu J, Kim WK, Song J, Chung HJ, et al. A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer. Biochem Pharm. 2018;158:84–94.

    CAS  PubMed  Google Scholar 

  27. Ruan D, He J, Li CF, Lee HJ, Liu J, Lin HK, et al. Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist. Oncogene. 2017;36:4299–310.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tian YF, Chen TJ, Lin CY, Chen LT, Lin LC, Hsing CH, et al. SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential. Tumour Biol. 2013;34:1107–17.

    CAS  PubMed  Google Scholar 

  29. Fu HC, Yang YC, Chen YJ, Lin H, Ou YC, Chien CC, et al. Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation. Oncotarget. 2016;7:44047–61.

    PubMed  PubMed Central  Google Scholar 

  30. Bijur GN, Jope RS. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem. 2003;87:1427–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Su CC, Yang JY, Leu HB, Chen Y, Wang PH. Mitochondrial Akt-regulated mitochondrial apoptosis signaling in cardiac muscle cells. Am J Physiol Heart Circ Physiol. 2012;302:H716–723.

    CAS  PubMed  Google Scholar 

  32. Ghosh JC, Siegelin MD, Vaira V, Faversani A, Tavecchio M, Chae YC, et al. Adaptive mitochondrial reprogramming and resistance to PI3K therapy. J Natl Cancer Inst. 2015;107:dju502.

    PubMed  PubMed Central  Google Scholar 

  33. Chae YC, Vaira V, Caino MC, Tang HY, Seo JH, Kossenkov AV, et al. Mitochondrial Akt regulation of hypoxic tumor reprogramming. Cancer Cell. 2016;30:257–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee AW, Lau WH, Tung SY, Chua DT, Chappell R, Xu L, et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol. 2005;23:6966–75.

    CAS  PubMed  Google Scholar 

  35. Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol. 2015;33:3356–64.

    PubMed  Google Scholar 

  36. Bissey PA, Law JH, Bruce JP, Shi W, Renoult A, Chua MLK, et al. Dysregulation of the MiR-449b target TGFBI alters the TGFbeta pathway to induce cisplatin resistance in nasopharyngeal carcinoma. Oncogenesis. 2018;7:40.

    PubMed  PubMed Central  Google Scholar 

  37. Liu F, Tai Y, Ma J. LncRNA NEAT1/let-7a-5p axis regulates the cisplatin resistance in nasopharyngeal carcinoma by targeting Rsf-1 and modulating the Ras-MAPK pathway. Cancer Biol Ther. 2018;19:534–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Li S, Zhang X, Zhang R, Liang Z, Liao W, Du Z, et al. Hippo pathway contributes to cisplatin resistant-induced EMT in nasopharyngeal carcinoma cells. Cell Cycle. 2017;16:1601–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhen Y, Fang W, Zhao M, Luo R, Liu Y, Fu Q, et al. miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin. Oncogene. 2017;36:275–85.

    CAS  PubMed  Google Scholar 

  40. Gao W, Li JZ, Chen SQ, Chu CY, Chan JY, Wong TS. BEX3 contributes to cisplatin chemoresistance in nasopharyngeal carcinoma. Cancer Med. 2017;6:439–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Feng S, Yang G, Yang H, Liang Z, Zhang R, Fan Y, et al. NEDD4 is involved in acquisition of epithelial-mesenchymal transition in cisplatin-resistant nasopharyngeal carcinoma cells. Cell Cycle. 2017;16:869–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Xie P, Yang JP, Cao Y, Peng LX, Zheng LS, Sun R, et al. Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target. Cell Death Dis. 2017;8:e2834.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kuang CM, Fu X, Hua YJ, Shuai WD, Ye ZH, Li Y, et al. BST2 confers cisplatin resistance via NF-kappaB signaling in nasopharyngeal cancer. Cell Death Dis. 2017;8:e2874.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell. 2004;16:819–30.

    CAS  PubMed  Google Scholar 

  45. Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem. 2002;277:7610–8.

    CAS  PubMed  Google Scholar 

  46. Zhang XY, Zhang M, Cong Q, Zhang MX, Zhang MY, Lu YY, et al. Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy. Int J Biochem Cell Biol. 2018;95:9–16.

    CAS  PubMed  Google Scholar 

  47. Cheng C, Xie Z, Li Y, Wang J, Qin C, Zhang Y. PTBP1 knockdown overcomes the resistance to vincristine and oxaliplatin in drug-resistant colon cancer cells through regulation of glycolysis. Biomed Pharmacol. 2018;108:194–200.

    CAS  Google Scholar 

  48. Li S, Li J, Dai W, Zhang Q, Feng J, Wu L, et al. Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death. Br J Cancer. 2017;117:1518–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Fan L, Huang C, Li J, Gao T, Lin Z, Yao T. Long noncoding RNA urothelial cancer associated 1 regulates radioresistance via the hexokinase 2/glycolytic pathway in cervical cancer. Int J Mol Med. 2018;42:2247–59.

    CAS  PubMed  Google Scholar 

  50. Mair R, Wright AJ, Ros S, Hu DE, Booth T, Kreis F, et al. Metabolic imaging detects low levels of glycolytic activity that vary with levels of c-Myc expression in patient-derived xenograft models of glioblastoma. Cancer Res. 2018;78:5408–18.

    CAS  PubMed  Google Scholar 

  51. Yang T, Ren C, Qiao P, Han X, Wang L, Lv S, et al. PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. Oncogene. 2018;37:5997–6009.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Xiao L, Hu ZY, Dong X, Tan Z, Li W, Tang M, et al. Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene. 2014;33:4568–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chan CH, Morrow JK, Li CF, Gao Y, Jin G, Moten A, et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell. 2013;154:556–68.

    CAS  PubMed  Google Scholar 

  54. Li W, Yu X, Ma X, Xie L, Xia Z, Liu L, et al. Deguelin attenuates non-small cell lung cancer cell metastasis through inhibiting the CtsZ/FAK signaling pathway. Cell Signal. 2018;50:131–41.

    CAS  PubMed  Google Scholar 

  55. Li W, Yu X, Xia Z, Yu X, Xie L, Ma X, et al. Repression of Noxa by Bmi1 contributes to deguelin-induced apoptosis in non-small cell lung cancer cells. J Cell Mol Med. 2018;22:6213–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu H, Li W, Yu X, Gao F, Duan Z, Ma X, et al. EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis. Oncotarget. 2016;7:56338–54.

    PubMed  PubMed Central  Google Scholar 

  57. Yu X, Li W, Deng Q, You S, Liu H, Peng S, et al. Neoalbaconol inhibits angiogenesis and tumor growth by suppressing EGFR-mediated VEGF production. Mol Carcinog. 2017;56:1414–26.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81572280, 81502121, and 81401548), the Natural Science Foundation of Hunan Province (2018JJ3787 and 2019JJ40420), and the New Xiangya Talent Project of the Third Xiangya Hospital of Central South University (No. JY2015011).

Author information

Author notes

  1. These authors are contributed equally: Xinfang Yu, Ruike Wang, Yangnan Zhang

Authors and Affiliations

  1. Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, PR China

    Xinfang Yu & Haidan Liu

  2. Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, PR China

    Xinfang Yu & Haidan Liu

  3. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Xinfang Yu

  4. Xiangya School of Medicine, Central South University, Changsha, 410000, Hunan, PR China

    Ruike Wang & Yangnan Zhang

  5. Department of Pathology, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, PR China

    Li Zhou

  6. Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, 410000, Hunan, PR China

    Wei Wang & Wei Li

Authors
  1. Xinfang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruike Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yangnan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haidan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wei Wang, Haidan Liu or Wei Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Yu, X., Wang, R., Zhang, Y. et al. Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin. Oncogene 38, 7457–7472 (2019). https://doi.org/10.1038/s41388-019-0955-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0955-7

This article is cited by

Search

Advanced search

Quick links