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

Xu,Li; Tang,Hailong; Wang,Kai; Zheng,Yanhua; Feng,Juan; Dong,Hongjuan; Jin,Yulong; Cao,Chun; Chen,Xiequn; Gao,Guangxun

doi:10.3892/mmr.2019.10075

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

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
Published online on: March 21, 2019 https://doi.org/10.3892/mmr.2019.10075
Pages: 4249-4255
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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

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