17. Yuan Y, Wang Q, Paulk J, Kubicek S, Kemp MM, Adams DJ, Shamji AF, Wagner BK,
Schreiber SL (2012) A small-molecule probe of the histone methyltransferase G9a induces
cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol 7(7):1152–1157. https://
doi.org/10.1021/cb300139y
18. Cherblanc FL, Chapman KL, Brown R, Fuchter MJ (2013) Chaetocin is a nonspecific inhibitor
of histone lysine methyltransferases. Nat Chem Biol 9(3):136–137. https://doi.org/10.1038/
nchembio.1187
19. Devkota K, Lohse B, Liu Q, Wang MW, Staerk D, Berthelsen J, Clausen RP (2014)
Analogues of the natural product sinefungin as inhibitors of EHMT1 and EHMT2. ACS
Med Chem Lett 5(4):293–297. https://doi.org/10.1021/ml4002503
20. Kondengaden SM, Luo LF, Huang K, Zhu M, Zang L, Bataba E, Wang R, Luo C, Wang B, Li
KK, Wang PG (2016) Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines. Eur J Med Chem 122:382–393.
https://doi.org/10.1016/j.ejmech.2016.06.028
21. Herz HM, Garruss A, Shilatifard A (2013) SET for life: biochemical activities and biological
functions of SET domain-containing proteins. Trends Biochem Sci 38(12):621–639. https://
doi.org/10.1016/j.tibs.2013.09.004
22. Lawson KA, Teteak CJ, Gao J, Li N, Hacquebord J, Ghatan A, Zielinska-Kwiatkowska A,
Song G, Chansky HA, Yang L (2013) ESET histone methyltransferase regulates osteoblastic
differentiation of mesenchymal stem cells during postnatal bone development. FEBS Lett 587
(24):3961–3967. https://doi.org/10.1016/j.febslet.2013.10.028
23. Karanth AV, Maniswami RR, Prashanth S, Govindaraj H, Padmavathy R, Jegatheesan SK,
Mullangi R, Rajagopal S (2017) Emerging role of SETDB1 as a therapeutic target.
Expert Opin Ther Targets 21(3):319–331. https://doi.org/10.1080/14728222.2017.1279604
24. Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD
(2003) Histone methyltransferases direct different degrees of methylation to define distinct
chromatin domains. Mol Cell 12(6):1591–1598
25. Loyola A, Bonaldi T, Roche D, Imhof A, Almouzni G (2006) PTMs on H3 variants before
chromatin assembly potentiate their final epigenetic state. Mol Cell 24(2):309–316. https://doi.
org/10.1016/j.molcel.2006.08.019
26. Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, Weipoltshammer K,
Pagani M, Lachner M, Kohlmaier A, Opravil S, Doyle M, Sibilia M, Jenuwein T (2001) Loss
of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome
stability. Cell 107(3):323–337
27. Muramatsu D, Singh PB, Kimura H, Tachibana M, Shinkai Y (2013) Pericentric heterochromatin generated by HP1 protein interaction-defective histone methyltransferase
Suv39h1. J Biol Chem 288(35):25285–25296. https://doi.org/10.1074/jbc.M113.470724
28. Sone K, Piao L, Nakakido M, Ueda K, Jenuwein T, Nakamura Y, Hamamoto R (2014)
Critical role of lysine 134 methylation on histone H2AX for gamma-H2AX production and
DNA repair. Nat Commun 5:5691. https://doi.org/10.1038/ncomms6691
29. Friedman J, Cho WK, Chu CK, Keedy KS, Archin NM, Margolis DM, Karn J (2011)
Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of
Zeste 2. J Virol 85(17):9078–9089. https://doi.org/10.1128/JVI.00836-11
30. Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific
inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem Biol 1(3):143–145. https://
doi.org/10.1038/nchembio721
31. Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2013) Reply to “Chaetocin is a
nonspecific inhibitor of histone lysine methyltransferases”. Nat Chem Biol 9(3):137. https://
doi.org/10.1038/nchembio.1188
32. Chaib H, Nebbioso A, Prebet T, Castellano R, Garbit S, Restouin A, Vey N, Altucci L, Collette
Y (2012) Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and
dual modulation of the histone methyl-transferase SUV39H1. Leukemia 26(4):662–674.
https://doi.org/10.1038/leu.2011.271
Lysine Methyltransferases and Their Inhibitors
149
Schreiber SL (2012) A small-molecule probe of the histone methyltransferase G9a induces
cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol 7(7):1152–1157. https://
doi.org/10.1021/cb300139y
18. Cherblanc FL, Chapman KL, Brown R, Fuchter MJ (2013) Chaetocin is a nonspecific inhibitor
of histone lysine methyltransferases. Nat Chem Biol 9(3):136–137. https://doi.org/10.1038/
nchembio.1187
19. Devkota K, Lohse B, Liu Q, Wang MW, Staerk D, Berthelsen J, Clausen RP (2014)
Analogues of the natural product sinefungin as inhibitors of EHMT1 and EHMT2. ACS
Med Chem Lett 5(4):293–297. https://doi.org/10.1021/ml4002503
20. Kondengaden SM, Luo LF, Huang K, Zhu M, Zang L, Bataba E, Wang R, Luo C, Wang B, Li
KK, Wang PG (2016) Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines. Eur J Med Chem 122:382–393.
https://doi.org/10.1016/j.ejmech.2016.06.028
21. Herz HM, Garruss A, Shilatifard A (2013) SET for life: biochemical activities and biological
functions of SET domain-containing proteins. Trends Biochem Sci 38(12):621–639. https://
doi.org/10.1016/j.tibs.2013.09.004
22. Lawson KA, Teteak CJ, Gao J, Li N, Hacquebord J, Ghatan A, Zielinska-Kwiatkowska A,
Song G, Chansky HA, Yang L (2013) ESET histone methyltransferase regulates osteoblastic
differentiation of mesenchymal stem cells during postnatal bone development. FEBS Lett 587
(24):3961–3967. https://doi.org/10.1016/j.febslet.2013.10.028
23. Karanth AV, Maniswami RR, Prashanth S, Govindaraj H, Padmavathy R, Jegatheesan SK,
Mullangi R, Rajagopal S (2017) Emerging role of SETDB1 as a therapeutic target.
Expert Opin Ther Targets 21(3):319–331. https://doi.org/10.1080/14728222.2017.1279604
24. Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD
(2003) Histone methyltransferases direct different degrees of methylation to define distinct
chromatin domains. Mol Cell 12(6):1591–1598
25. Loyola A, Bonaldi T, Roche D, Imhof A, Almouzni G (2006) PTMs on H3 variants before
chromatin assembly potentiate their final epigenetic state. Mol Cell 24(2):309–316. https://doi.
org/10.1016/j.molcel.2006.08.019
26. Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, Weipoltshammer K,
Pagani M, Lachner M, Kohlmaier A, Opravil S, Doyle M, Sibilia M, Jenuwein T (2001) Loss
of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome
stability. Cell 107(3):323–337
27. Muramatsu D, Singh PB, Kimura H, Tachibana M, Shinkai Y (2013) Pericentric heterochromatin generated by HP1 protein interaction-defective histone methyltransferase
Suv39h1. J Biol Chem 288(35):25285–25296. https://doi.org/10.1074/jbc.M113.470724
28. Sone K, Piao L, Nakakido M, Ueda K, Jenuwein T, Nakamura Y, Hamamoto R (2014)
Critical role of lysine 134 methylation on histone H2AX for gamma-H2AX production and
DNA repair. Nat Commun 5:5691. https://doi.org/10.1038/ncomms6691
29. Friedman J, Cho WK, Chu CK, Keedy KS, Archin NM, Margolis DM, Karn J (2011)
Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of
Zeste 2. J Virol 85(17):9078–9089. https://doi.org/10.1128/JVI.00836-11
30. Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific
inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem Biol 1(3):143–145. https://
doi.org/10.1038/nchembio721
31. Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2013) Reply to “Chaetocin is a
nonspecific inhibitor of histone lysine methyltransferases”. Nat Chem Biol 9(3):137. https://
doi.org/10.1038/nchembio.1188
32. Chaib H, Nebbioso A, Prebet T, Castellano R, Garbit S, Restouin A, Vey N, Altucci L, Collette
Y (2012) Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and
dual modulation of the histone methyl-transferase SUV39H1. Leukemia 26(4):662–674.
https://doi.org/10.1038/leu.2011.271
Lysine Methyltransferases and Their Inhibitors
149