Citation: Ren Yue, Sun Qinsheng, Yuan Zigao, Jiang Yuyang. Combined inhibition of HDAC and DNMT1 induces p85α/MEKmediated cell cycle arrest by dual target inhibitor 208 in U937 cells[J]. Chinese Chemical Letters, ;2019, 30(6): 1233-1236. doi: 10.1016/j.cclet.2019.03.029 shu

Combined inhibition of HDAC and DNMT1 induces p85α/MEKmediated cell cycle arrest by dual target inhibitor 208 in U937 cells

Ren Yue ^a,b,c,1 ,
Sun Qinsheng ^b,c,d,1 ,
Yuan Zigao ^b,c ,
Jiang Yuyang ^a,b,c,e,*,

a.
Department of Chemistry, Tsinghua University, Beijing 100084, China
b.
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
c.
National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, the Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
d.
School of Life Science, Tsinghua University, Beijing 100084, China
e.
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China

E-mail address:

jiangyy@sz.tsinghua.edu.cn

Received Date: 30 January 2019
Revised Date: 18 March 2019
Accepted Date: 19 March 2019
Available Online: 20 June 2019

Figures(4)

Multiple histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been developed for cancer therapy. However, the research on their mechanisms of action is not sophisticated enough. In this study, we reported a dual HDAC and DNMT inhibitor 208 and found it induced G1 cell cycle arrest and apoptosis in U937 cells. Proteome and bioinformatic analyses revealed that the combined inhibition of DNMT1 and HDAC by 208 affected the expression of a series of proteins involved in many biological processes. We observed that several proteins associated with G1 cell cycle arrest and apoptosis were down regulated after 208 treatment, including p85α, MEK, and CDK4, suggesting that 208 induces cell cycle arrest and apoptosis through the p85α/MEK-mediated pathway in U937 cells. Moreover, biological function analysis showed that the combined epigenetic inhibition influenced various processes, including the synthesis and processing of RNA, translation, protein transport, and DNA repair. These findings provide novel insight into the potential mechanisms of multifunctional epigenetic inhibitors, which supports their further improvement and development.
- Proteomics,
- Epigenetic inhibitor,
- HDAC,
- DNMT1,
- Cell cycle arrest
1. [1]
  M.A. Dawson, T. Kouzarides, Cell 150(2012) 12-27. doi: 10.1016/j.cell.2012.06.013
2. [2]
  M.D. Shahbazian, M. Grunstein, Annu. Rev. Biochem. 76(2007) 75-100. doi: 10.1146/annurev.biochem.76.052705.162114
3. [3]
  L. Wang, H. Li, Y. Ren, et al., Cell Death Dis. 7(2016) 2063. doi: 10.1038/cddis.2015.328
4. [4]
  K. Xue, J.J. Gu, Q. Zhang, et al., J. Cancer Res. Clin. Oncol. 142(2016) 379-387. doi: 10.1007/s00432-015-2026-y
5. [5]
  B. Kumar, A. Yadav, J.C. Lang, et al., Genes Cancer 6(2015) 169-181.
6. [6]
  F. Thaler, L. Moretti, R. Amici, et al., Eur. J. Med. Chem. 108(2016) 53-67. doi: 10.1016/j.ejmech.2015.11.010
7. [7]
  J. Roche, P. Bertrand, Eur. J. Med. Chem. 121(2016) 451-483. doi: 10.1016/j.ejmech.2016.05.047
8. [8]
  C.J. Gong, A.H. Gao, Y.M. Zhang, et al., Eur. J. Med. Chem. 112(2016) 81-90. doi: 10.1016/j.ejmech.2016.02.003
9. [9]
  A.C. West, R.W. Johnstone, J. Clin. Invest. 124(2014) 30-39. doi: 10.1172/JCI69738
10. [10]
  S. Yoon, G.H. Eom, Chonnam Med. J. 52(2016) 1-11. doi: 10.4068/cmj.2016.52.1.1
11. [11]
  Y. Shi, B. Jia, W. Xu, et al., J. Hematol. Oncol. 10(2017) 69. doi: 10.1186/s13045-017-0439-6
12. [12]
  K.J. Falkenberg, R.W. Johnstone, Nat. Rev. Drug Discov. 13(2014) 673-691. doi: 10.1038/nrd4360
13. [13]
  H.M. Hesham, D.S. Lasheen, K.A.M.Abouzid, Med. Res. Rev. 38(2018) 2058-2109. doi: 10.1002/med.2018.38.issue-6
14. [14]
  C. Manzoni, D.A. Kia, J. Vandrovcova, et al., Briefings Bioinf. 19(2018) 286-302. doi: 10.1093/bib/bbw114
15. [15]
  V.G. Anania, J.R. Lill, Proteomics:Clin. Appl. 9(2015) 671-683. doi: 10.1002/prca.v9.7-8
16. [16]
  R. Aebersold, M. Mann, Nature 537(2016) 347-355. doi: 10.1038/nature19949
17. [17]
  Y. Zhao, S. Miriyala, L. Miao, et al., Free Rad. Biol. Med. 72(2014) 55-65. doi: 10.1016/j.freeradbiomed.2014.03.001
18. [18]
  J. Lin, X.D. Li, Chin. Chem. Lett. 29(2018) 1051-1057. doi: 10.1016/j.cclet.2018.05.017
19. [19]
  M. Breker, M. Schuldiner, Nat. Rev. Mol. Cell Biol. 15(2014) 453-464. doi: 10.1038/nrm3821
20. [20]
  R. Pathania, S. Ramachandran, G. Mariappan, et al., Cancer Res. 76(2016) 3224-3235. doi: 10.1158/0008-5472.CAN-15-2249
21. [21]
  N. Azad, C.A. Zahnow, C.M. Rudin, S.B. Baylin, Nat. Rev. Clin. Oncol. 10(2013) 256-266. doi: 10.1038/nrclinonc.2013.42
22. [22]
  R.A. Juergens, J. Wrangle, F.P. Vendetti, et al., Cancer Discov. 1(2011) 598-607. doi: 10.1158/2159-8290.CD-11-0214
23. [23]
  E.A. Griffiths, S.D. Gore, Semin. Hematol. 45(2008) 23-30. doi: 10.1053/j.seminhematol.2007.11.007
24. [24]
  Z. Cui, X. Li, L. Li, et al., Bioorg. Med. Chem. 24(2016) 261-269. doi: 10.1016/j.bmc.2015.12.011
25. [25]
  W. Zhang, B. Zhang, W. Zhang, et al., Eur. J. Med. Chem. 116(2016) 59-70. doi: 10.1016/j.ejmech.2016.03.066
26. [26]
  C. Ding, D. Li, Y.W. Wang, et al., Chin. Chem. Lett. 28(2017) 1220-1227. doi: 10.1016/j.cclet.2017.01.003
27. [27]
  Z. Yuan, Q. Sun, D. Li, et al., Eur. J. Med. Chem. 134(2017) 281-292. doi: 10.1016/j.ejmech.2017.04.017
28. [28]
  S. Chen, Y. Wang, W. Zhou, et al., J. Med. Chem. 57(2014) 9028-9041. doi: 10.1021/jm501134e
29. [29]
  A. Scuto, M. Kirschbaum, C. Kowolik, et al., Blood 111(2008) 5093-5100. doi: 10.1182/blood-2007-10-117762
30. [30]
  J. Datta, K. Ghoshal, W.A. Denny, et al., Cancer Res. 69(2009) 4277-4285. doi: 10.1158/0008-5472.CAN-08-3669
31. [31]
  A.K. Witkiewicz, K.E. Knudsen, A.P. Dicker, E.S. Knudsen, Cell Cycle 10(2011) 2497-2503. doi: 10.4161/cc.10.15.16776
32. [32]
  D. Hanahan, R.A. Weinberg, Cell 144(2011) 646-674. doi: 10.1016/j.cell.2011.02.013
33. [33]
  K. Ha, W. Fiskus, D.S. Choi, et al., Oncotarget 5(2014) 5637-5650.
34. [34]
  Q. Wu, W. Xu, L. Cao, et al., J. Proteome Res. 12(2013) 4064-4073. doi: 10.1021/pr4004079
35. [35]
  H.G. Zhang, W.E. Grizzlet, Am. J. Pathol. 184(2014) 28-41. doi: 10.1016/j.ajpath.2013.09.027
36. [36]
  M.S. Sosa, C. Lopez-Haber, C. Yang, et al., Mol. Cell 40(2010) 877-892. doi: 10.1016/j.molcel.2010.11.029
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