Tumor Biology

, Volume 35, Issue 7, pp 6357–6363 | Cite as

High-mobility group nucleosome-binding domain 5 increases drug resistance in osteosarcoma through upregulating autophagy

  • Chaoqun Yang
  • Rui Gao
  • Jirong Wang
  • Wen Yuan
  • Ce Wang
  • Xuhui Zhou
Research Article


Although tumor therapy has been improved in the past decades, the survival outcomes for osteosarcoma remain unsatisfactory, and one of the primary reasons for the failure of current treatment is that patients with late-stage cancer often develop resistance to anticancer drugs. High-mobility group nucleosome-binding domain 5 (HMGN5) is a newly identified gene associated with cancer and autophagy, which could inhibit apoptosis induced by anticancer agents. However, it is still unclear whether HMGN5 regulated autophagy in osteosarcoma, and the mechanism and significance of HMGN5-mediated autophagy in tumor therapy is never investigated. In this study, we first detected HMGN5 in vivo and in vitro. HMGN5 was highly expressed in osteosarcoma tumor, especially in posttreatment tumor. Next, we employed adenovirus-mediated overexpression of HMGN5 in U-2OS and MG63 to investigate the role of HMGN5 in osteosarcoma cell lines. Adenovirus-mediated overexpression of HMGN5 could efficiently upregulate the expression level of HMGN5 in osteosarcoma cell lines at both messenger RNA (mRNA) and protein levels. Anticancer agents namely doxorubicin, cisplatin, and methotrexate each induced HMGN5 upregulation in human U-2OS and MG63 osteosarcoma cell lines. In addition, overexpression of HMGN5 reduced the chemosensitivity of osteosarcoma cells in vitro, and the mechanistic investigation revealed that HMGN5 increased drug resistance by upregulating autophagy. Therefore, HMGN5 is a critical factor in the development of chemoresistance through regulating autophagy, and it offers a novel target for improving osteosarcoma therapy.


High-mobility group nucleosome-binding domain 5 Osteosarcoma Autophagy Chemosensitivity 


Conflicts of interest



  1. 1.
    Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13. doi: 10.1007/978-1-4419-0284-9_1.CrossRefPubMedGoogle Scholar
  2. 2.
    Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol. 2008;26(4):633–8. doi: 10.1200/JCO.2008.14.0095.CrossRefPubMedGoogle Scholar
  3. 3.
    Gill M, McCarthy M, Murrells T, Silcocks P. Chemotherapy for the primary treatment of osteosarcoma: population effectiveness over 20 years. Lancet. 1988;1(8587):689–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Desandes E. Survival from adolescent cancer. Cancer Treat Rev. 2007;33(7):609–15. doi: 10.1016/j.ctrv.2006.12.007.CrossRefPubMedGoogle Scholar
  5. 5.
    Bustin M, Reeves R. High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol. 1996;54:35–100.CrossRefPubMedGoogle Scholar
  6. 6.
    Bustin M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol. 1999;19(8):5237–46.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Rochman M, Malicet C, Bustin M. HMGN5/HMGN5: a new member of the HMGN protein family that affects chromatin structure and function. Biochim Biophys Acta. 2010;1799(1–2):86–92. doi: 10.1016/j.bbagrm.2009.09.012.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Huang C, Zhou LQ, Song G. Effect of nucleosomal binding protein 1 in androgen-independent prostatic carcinoma. Zhonghua Yi Xue Za Zhi. 2008;88(10):657–60.PubMedGoogle Scholar
  9. 9.
    Green J, Ikram M, Vyas J, Patel N, Proby CM, Ghali L, et al. Overexpression of the Axl tyrosine kinase receptor in cutaneous SCC-derived cell lines and tumours. Br J Cancer. 2006;94(10):1446–51. doi: 10.1038/sj.bjc.6603135.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Tang WY, Newbold R, Mardilovich K, Jefferson W, Cheng RY, Medvedovic M, et al. Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (HMGN5) correlates with overexpression of HMGN5 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology. 2008;149(12):5922–31. doi: 10.1210/en.2008-0682.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Li DQ, Hou YF, Wu J, Chen Y, Lu JS, Di GH, et al. Gene expression profile analysis of an isogenic tumour metastasis model reveals a functional role for oncogene AF1Q in breast cancer metastasis. Eur J Cancer. 2006;42(18):3274–86. doi: 10.1016/j.ejca.2006.07.008.CrossRefPubMedGoogle Scholar
  12. 12.
    Bincoletto C, Bechara A, Pereira GJ, Santos CP, Antunes F. Peixoto da-Silva J et al. Interplay between apoptosis and autophagy, a challenging puzzle: new perspectives on antitumor chemotherapies. Chem Biol Interact. 2013;206(2):279–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Kumar D, Shankar S, Srivastava RK. Rottlerin-induced autophagy leads to the apoptosis in breast cancer stem cells: molecular mechanisms. Mol Cancer. 2013;12(1):171. doi: 10.1186/1476-4598-12-171.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Lee JW, Kim KS, An HK, Kim CH, Moon HI, Lee YC. Dendropanoxide induces autophagy through ERK1/2 activation in MG-63 human osteosarcoma cells and autophagy inhibition enhances dendropanoxide-induced apoptosis. PLoS One. 2013;8(12):e83611. doi: 10.1371/journal.pone.0083611.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Zhao Z, Tao L, Shen C, Liu B, Yang Z, Tao H. Silencing of Barkor/ATG14 sensitizes osteosarcoma cells to cisplatin-induced apoptosis. Int J Mol Med. 2014;33(2):271–6. doi: 10.3892/ijmm.2013.1578.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Xie ZG, Xie Y, Dong QR. Inhibition of the mammalian target of rapamycin leads to autophagy activation and cell death of MG63 osteosarcoma cells. Oncol Lett. 2013;6(5):1465–9. doi: 10.3892/ol.2013.1531.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R, et al. HMGB1 promotes drug resistance in osteosarcoma. Cancer Res. 2012;72(1):230–8. doi: 10.1158/0008-5472.CAN-11-2001.CrossRefPubMedGoogle Scholar
  18. 18.
    Wahafu W, He ZS, Zhang XY, Zhang CJ, Yao K, Hao H, et al. The nucleosome binding protein HMGN5 is highly expressed in human bladder cancer and promotes the proliferation and invasion of bladder cancer cells. Tumour Biol. 2011;32(5):931–9. doi: 10.1007/s13277-011-0195-0.CrossRefPubMedGoogle Scholar
  19. 19.
    Lanvers-Kaminsky C, Winter B, Koling S, Frodermann B, Braun Y, Schaefer KL, et al. Doxorubicin modulates telomerase activity in Ewing’s sarcoma in vitro and in vivo. Oncol Rep. 2005;14(3):751–8.PubMedGoogle Scholar
  20. 20.
    Dirks-Naylor AJ. The role of autophagy in doxorubicin-induced cardiotoxicity. Life Sci. 2013;93(24):913–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26. doi: 10.1016/j.cell.2010.01.028.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Yang YH, Chen K, Li B, Chen JW, Zheng XF, Wang YR, et al. Estradiol inhibits osteoblast apoptosis via promotion of autophagy through the ER-ERK-mTOR pathway. Apoptosis. 2013. doi: 10.1007/s10495-013-0867-x.Google Scholar
  23. 23.
    Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5(9):726–34. doi: 10.1038/nrc1692.CrossRefPubMedGoogle Scholar
  24. 24.
    Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011;17(4):654–66. doi: 10.1158/1078-0432.CCR-10-2634.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40(2):280–93. doi: 10.1016/j.molcel.2010.09.023.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Chaoqun Yang
    • 1
  • Rui Gao
    • 1
  • Jirong Wang
    • 2
  • Wen Yuan
    • 1
  • Ce Wang
    • 1
  • Xuhui Zhou
    • 1
  1. 1.Department of Orthopedic Surgery, Changzheng HospitalSecond Military Medical UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Orthopedic SurgeryPLA 273th HospitalKorlaChina

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