33. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D
(2008) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell
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34. Ketel CS, Andersen EF, Vargas ML, Suh J, Strome S, Simon JA (2005) Subunit contributions
to histone methyltransferase activities of fly and worm polycomb group complexes. Mol Cell
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35. Vasanthakumar A, Xu D, Lun AT, Kueh AJ, van Gisbergen KP, Iannarella N, Li X, Yu L,
Wang D, Williams BR, Lee SC, Majewski IJ, Godfrey DI, Smyth GK, Alexander WS,
Herold MJ, Kallies A, Nutt SL, Allan RS (2017) A non-canonical function of Ezh2 preserves
immune homeostasis. EMBO Rep 18(4):619–631. https://doi.org/10.15252/embr.201643237
36. Kim KH, Roberts CW (2016) Targeting EZH2 in cancer. Nat Med 22(2):128–134. https://doi.
org/10.1038/nm.4036
37. Margueron R, Reinberg D (2011) The Polycomb complex PRC2 and its mark in life.
Nature 469(7330):343–349. https://doi.org/10.1038/nature09784
38. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone
SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell
GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP,
Melton DA, Gifford DK, Jaenisch R, Young RA (2006) Control of developmental regulators
by Polycomb in human embryonic stem cells. Cell 125(2):301–313. https://doi.org/10.1016/j.
cell.2006.02.043
39. Nichol JN, Dupere-Richer D, Ezponda T, Licht JD, Miller WHJ (2016) H3K27 methylation: a
focal point of epigenetic deregulation in cancer. Adv Cancer Res 131:59–95. https://doi.org/
10.1016/bs.acr.2016.05.001
40. Glazer RI, Knode MC, Tseng CK, Haines DR, Marquez VE (1986) 3-Deazaneplanocin A: a
new inhibitor of S-adenosylhomocysteine synthesis and its effects in human colon carcinoma
cells. Biochem Pharmacol 35(24):4523–4527
41. Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA (2009)
DZNep is a global histone methylation inhibitor that reactivates developmental genes not
silenced by DNA methylation. Mol Cancer Ther 8(6):1579–1588. https://doi.org/10.1158/
1535-7163.MCT-09-0013
42. Sun F, Lee L, Zhang Z, Wang X, Yu Q, Duan X, Chan E (2015) Preclinical pharmacokinetic
studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus. Eur J Pharm Sci 77:290–302. https://doi.org/10.1016/j.
ejps.2015.06.021
43. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD,
Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer
MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW (2012) A selective
inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem
Biol 8(11):890–896. https://doi.org/10.1038/nchembio.1084
44. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, Smitheman KN, Ott HM,
Pappalardi MB, Allen KE, Chen SB, Della Pietra 3rd A, Dul E, Hughes AM, Gilbert SA,
Thrall SH, Tummino PJ, Kruger RG, Brandt M, Schwartz B, Creasy CL (2012) Mutation of
A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A 109(8):
2989–2994. https://doi.org/10.1073/pnas.1116418109
45. Yap TA, Winter JN, Leonard JP, Ribrag V, Constantinidou A, Giulino-Roth L, Michot J-M,
Khan TA, Horner T, Carver J, Pene Dumetrescu T, He Z, McCabe MT, Creasy CL, Dhar A,
Carpenter C, Johnson PM (2016) A phase I study of GSK2816126, an enhancer of zeste
homolog 2(EZH2) inhibitor, in patients (pts) with relapsed/refractory diffuse large B-cell
lymphoma (DLBCL), other non-Hodgkin lymphomas (NHL), transformed follicular lymphoma (tFL), solid tumors and multiple myeloma (MM). Blood 128(22):4203
46. Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, Newlander KA, Romeril SP,
Burgess JL, Grant SW, Brackley JA, Graves AP, Scherzer DA, Shu A, Thompson C, Ott HM,
150
G. Stazi et al.
(2008) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell
32(4):503–518. https://doi.org/10.1016/j.molcel.2008.11.004
34. Ketel CS, Andersen EF, Vargas ML, Suh J, Strome S, Simon JA (2005) Subunit contributions
to histone methyltransferase activities of fly and worm polycomb group complexes. Mol Cell
Biol 25(16):6857–6868. https://doi.org/10.1128/MCB.25.16.6857-6868.2005
35. Vasanthakumar A, Xu D, Lun AT, Kueh AJ, van Gisbergen KP, Iannarella N, Li X, Yu L,
Wang D, Williams BR, Lee SC, Majewski IJ, Godfrey DI, Smyth GK, Alexander WS,
Herold MJ, Kallies A, Nutt SL, Allan RS (2017) A non-canonical function of Ezh2 preserves
immune homeostasis. EMBO Rep 18(4):619–631. https://doi.org/10.15252/embr.201643237
36. Kim KH, Roberts CW (2016) Targeting EZH2 in cancer. Nat Med 22(2):128–134. https://doi.
org/10.1038/nm.4036
37. Margueron R, Reinberg D (2011) The Polycomb complex PRC2 and its mark in life.
Nature 469(7330):343–349. https://doi.org/10.1038/nature09784
38. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone
SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell
GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP,
Melton DA, Gifford DK, Jaenisch R, Young RA (2006) Control of developmental regulators
by Polycomb in human embryonic stem cells. Cell 125(2):301–313. https://doi.org/10.1016/j.
cell.2006.02.043
39. Nichol JN, Dupere-Richer D, Ezponda T, Licht JD, Miller WHJ (2016) H3K27 methylation: a
focal point of epigenetic deregulation in cancer. Adv Cancer Res 131:59–95. https://doi.org/
10.1016/bs.acr.2016.05.001
40. Glazer RI, Knode MC, Tseng CK, Haines DR, Marquez VE (1986) 3-Deazaneplanocin A: a
new inhibitor of S-adenosylhomocysteine synthesis and its effects in human colon carcinoma
cells. Biochem Pharmacol 35(24):4523–4527
41. Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA (2009)
DZNep is a global histone methylation inhibitor that reactivates developmental genes not
silenced by DNA methylation. Mol Cancer Ther 8(6):1579–1588. https://doi.org/10.1158/
1535-7163.MCT-09-0013
42. Sun F, Lee L, Zhang Z, Wang X, Yu Q, Duan X, Chan E (2015) Preclinical pharmacokinetic
studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus. Eur J Pharm Sci 77:290–302. https://doi.org/10.1016/j.
ejps.2015.06.021
43. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD,
Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer
MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW (2012) A selective
inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem
Biol 8(11):890–896. https://doi.org/10.1038/nchembio.1084
44. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, Smitheman KN, Ott HM,
Pappalardi MB, Allen KE, Chen SB, Della Pietra 3rd A, Dul E, Hughes AM, Gilbert SA,
Thrall SH, Tummino PJ, Kruger RG, Brandt M, Schwartz B, Creasy CL (2012) Mutation of
A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A 109(8):
2989–2994. https://doi.org/10.1073/pnas.1116418109
45. Yap TA, Winter JN, Leonard JP, Ribrag V, Constantinidou A, Giulino-Roth L, Michot J-M,
Khan TA, Horner T, Carver J, Pene Dumetrescu T, He Z, McCabe MT, Creasy CL, Dhar A,
Carpenter C, Johnson PM (2016) A phase I study of GSK2816126, an enhancer of zeste
homolog 2(EZH2) inhibitor, in patients (pts) with relapsed/refractory diffuse large B-cell
lymphoma (DLBCL), other non-Hodgkin lymphomas (NHL), transformed follicular lymphoma (tFL), solid tumors and multiple myeloma (MM). Blood 128(22):4203
46. Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, Newlander KA, Romeril SP,
Burgess JL, Grant SW, Brackley JA, Graves AP, Scherzer DA, Shu A, Thompson C, Ott HM,
150
G. Stazi et al.