Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
May-2019 Volume 19 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
May-2019 Volume 19 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells

  • Authors:
    • Li Xu
    • Hailong Tang
    • Kai Wang
    • Yanhua Zheng
    • Juan Feng
    • Hongjuan Dong
    • Yulong Jin
    • Chun Cao
    • Xiequn Chen
    • Guangxun Gao
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, People's Liberation Army Center of Hematologic Disorders, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Gastroenterology, The 16th Hospital of the People's Liberation Army of China, Xinjiang 836599, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 4249-4255
    |
    Published online on: March 21, 2019
       https://doi.org/10.3892/mmr.2019.10075
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Enhancer of zeste homolog 2 (EZH2) serves a pivotal role in epigenetic silencing by acting as a histone methyltransferase. It has been confirmed that EZH2 overexpression occurs in different types of cancer and is involved in drug resistance, while it remains unclear how a DNA‑damaging event may promote EZH2 expression in multiple myeloma (MM) cells and how EZH2 influences its susceptibility to death in response to DNA‑damaging chemotherapy. The present study examined the impact of EZH2 inhibition on DNA damage‑induced apoptosis in MM cells and elucidated its underlying molecular mechanism. It was demonstrated that pharmacological inhibition of EZH2 sensitized MM cells to DNA‑damaging agents and promoted limited caspase‑dependent apoptosis. Mechanistically, targeting EZH2 with minimal toxic concentrations of a pharmacological inhibitor (GSK126) markedly weakened the accompanying increase in the histone trimethylation H3K27me3 and aggravated DNA damage response (DDR)‑associated apoptosis in vitro. These data preliminarily confirmed the underlying molecular mechanisms of interaction between histone methylation and the DDR in MM cells, forming the rationale for the combination regimen of EZH2 inhibitors with DNA‑damaging agents for the treatment of MM.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Pourabdollah M and Chang H: Coexistence of multiple myeloma and Paget disease of bone. Blood. 130:11732017. View Article : Google Scholar : PubMed/NCBI

2 

Mai EK, Bertsch U, Durig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, et al: Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 29:1721–1729. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Issa ME, Takhsha FS, Chirumamilla CS, Perez-Novo C, Vanden Berghe W and Cuendet M: Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clin Epigenetics. 9:172017. View Article : Google Scholar : PubMed/NCBI

4 

Pawlyn C, Kaiser MF, Davies FE and Morgan GJ: Current and potential epigenetic targets in multiple myeloma. Epigenomics. 6:215–228. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Sanulli S, Justin N, Teissandier A, Ancelin K, Portoso M, Caron M, Michaud A, Lombard B, da Rocha ST, Offer J, et al: Jarid2 methylation via the PRC2 complex regulates H3K27me3 deposition during cell differentiation. Mol Cell. 57:769–783. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Pawlyn C, Bright MD, Buros AF, Stein CK, Walters Z, Aronson LI, Mirabella F, Jones JR, Kaiser MF, Walker BA, et al: Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J. 7:e5492017. View Article : Google Scholar : PubMed/NCBI

7 

Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS and Zhang Y: Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 298:1039–1043. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Ito T, Teo YV, Evans SA, Neretti N and Sedivy JM: Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22:3480–3492. 2018. View Article : Google Scholar : PubMed/NCBI

9 

Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD and Kleer CG: The polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia. 7:1011–1019. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Ha K, Lee GE, Palii SS, Brown KD, Takeda Y, Liu K, Bhalla KN and Robertson KD: Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery. Hum Mol Genet. 20:126–140. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Kuroda J: Therapeutic approach for relapsed/refractory multiple myeloma: The logic and practice. Rinsho Ketsueki. 58:2058–2066. 2017.(In Japanese). PubMed/NCBI

12 

Varga C, Maglio M, Ghobrial IM and Richardson PG: Current use of monoclonal antibodies in the treatment of multiple myeloma. Br J Haematol. 181:447–459. 2018. View Article : Google Scholar : PubMed/NCBI

13 

Kuser-Abali G, Gong L, Yan J, Liu Q, Zeng W, Williamson A, Lim CB, Molloy ME, Little JB, Huang L and Yuan ZM: An EZH2-mediated epigenetic mechanism behind p53-dependent tissue sensitivity to DNA damage. Proc Natl Acad Sci USA. 115:3452–3457. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Wang J, Cheng P, Pavlyukov MS, Yu H, Zhang Z, Kim SH, Minata M, Mohyeldin A, Xie W, Chen D, et al: Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. J Clin Invest. 127:3075–3089. 2017. View Article : Google Scholar : PubMed/NCBI

15 

Wu Z, Lee ST, Qiao Y, Li Z, Lee PL, Lee YJ, Jiang X, Tan J, Aau M, Lim CZ and Yu Q: Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage. Cell Death Differ. 18:1771–1779. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Vissers JH, van Lohuizen M and Citterio E: The emerging role of Polycomb repressors in the response to DNA damage. J Cell Sci. 125:3939–3948. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Bouwman P and Jonkers J: The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 12:587–598. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Yang Q, Nair S, Laknaur A, Ismail N, Diamond MP and Al-Hendy A: The polycomb group protein EZH2 impairs DNA damage repair gene expression in human uterine fibroids. Biol Reprod. 94:692016. View Article : Google Scholar : PubMed/NCBI

19 

Liu H, Li W, Yu X, Gao F, Duan Z, Ma X, Tan S, Yuan Y, Liu L, Wang J, et al: EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis. Oncotarget. 7:56338–56354. 2016.PubMed/NCBI

20 

Zhou BB and Elledge SJ: The DNA damage response: Putting checkpoints in perspective. Nature. 408:433–439. 2000. View Article : Google Scholar : PubMed/NCBI

21 

Yan S, Sorrell M and Berman Z: Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress. Cell Mol Life Sci. 71:3951–3967. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Huang Y, Wang X, Niu X, Wang X, Jiang R, Xu T, Liu Y, Liang L, Ou X, Xing X, et al: EZH2 suppresses the nucleotide excision repair in nasopharyngeal carcinoma by silencing XPA gene. Mol Carcinog. 56:447–463. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Gursoy-Yuzugullu O, Carman C, Serafim RB, Myronakis M, Valente V and Price BD: Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity. Oncotarget. 8:24518–24532. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Kirk JS, Schaarschuch K, Dalimov Z, Lasorsa E, Ku S, Ramakrishnan S, Hu Q, Azabdaftari G, Wang J, Pili R and Ellis L: Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer. Oncotarget. 6:3136–3146. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Stamato MA, Juli G, Romeo E, Ronchetti D, Arbitrio M, Caracciolo D, Neri A, Tagliaferri P, Tassone P and Amodio N: Inhibition of EZH2 triggers the tumor suppressive miR-29b network in multiple myeloma. Oncotarget. 8:106527–106537. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Yu Q: Restoring p53-mediated apoptosis in cancer cells: New opportunities for cancer therapy. Drug Resist Updat. 9:19–25. 2006. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Xu L, Tang H, Wang K, Zheng Y, Feng J, Dong H, Jin Y, Cao C, Chen X, Gao G, Gao G, et al: Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells. Mol Med Rep 19: 4249-4255, 2019.
APA
Xu, L., Tang, H., Wang, K., Zheng, Y., Feng, J., Dong, H. ... Gao, G. (2019). Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells. Molecular Medicine Reports, 19, 4249-4255. https://doi.org/10.3892/mmr.2019.10075
MLA
Xu, L., Tang, H., Wang, K., Zheng, Y., Feng, J., Dong, H., Jin, Y., Cao, C., Chen, X., Gao, G."Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells". Molecular Medicine Reports 19.5 (2019): 4249-4255.
Chicago
Xu, L., Tang, H., Wang, K., Zheng, Y., Feng, J., Dong, H., Jin, Y., Cao, C., Chen, X., Gao, G."Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells". Molecular Medicine Reports 19, no. 5 (2019): 4249-4255. https://doi.org/10.3892/mmr.2019.10075
Copy and paste a formatted citation
x
Spandidos Publications style
Xu L, Tang H, Wang K, Zheng Y, Feng J, Dong H, Jin Y, Cao C, Chen X, Gao G, Gao G, et al: Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells. Mol Med Rep 19: 4249-4255, 2019.
APA
Xu, L., Tang, H., Wang, K., Zheng, Y., Feng, J., Dong, H. ... Gao, G. (2019). Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells. Molecular Medicine Reports, 19, 4249-4255. https://doi.org/10.3892/mmr.2019.10075
MLA
Xu, L., Tang, H., Wang, K., Zheng, Y., Feng, J., Dong, H., Jin, Y., Cao, C., Chen, X., Gao, G."Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells". Molecular Medicine Reports 19.5 (2019): 4249-4255.
Chicago
Xu, L., Tang, H., Wang, K., Zheng, Y., Feng, J., Dong, H., Jin, Y., Cao, C., Chen, X., Gao, G."Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells". Molecular Medicine Reports 19, no. 5 (2019): 4249-4255. https://doi.org/10.3892/mmr.2019.10075
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team