Review
Copyright ©The Author(s) 2019.
World J Stem Cells. Nov 26, 2019; 11(11): 920-936
Published online Nov 26, 2019. doi: 10.4252/wjsc.v11.i11.920
Table 1 Negative correlation between combined expression of cancer stem cell markers CD133, CD44 and CD166 and epigenetic writers
Family/gene symbolEpidrug/chemical probeClinical trials for CRCResults/statusZ-scoreP value
DNA methyltransferases5-azacytidine (Vidaza)1Early Phase I to phase II[63,64]No OR[63,65]
5-aza-2’-désoxycytidine (Decitabine)1Phase I to phase II[66-68]No OR[66]; beneficial with Panitumumab[68]
EGCG (Green tea extract)Preclinical spheroid-derived cancer stem cell xenograft models[69]Sensitization to chemotherapy
ZebularinePreclinical xenografts[70]Anticancer activity
RG108, Procainamide2
DNMT3A, DNMT3B, DNMT3L-2.788/-4.848/-4.321< 0.005
Activating Lysine methyltransferases
SETD6vp22-RelA302-3163[71]-4.6413.47E-06
SETD1A-4.3751.212E-05
Repressive Lysine methyltransferases
SMYD5--4.5146.371E-06
EHMT2UNC02243, UNC06423, BIX-012943-4.3221.545E-05
SETDB2--3.60.0003176
PRDM13--3.442< 0.005
SUV39H1, SUV39H2Chaetocin3-3.422/-2.9340.0006216
PRDM12--3.0890.00201
EZH1UNC19993-2.7870.005314
EZH2CPI-12052,4, EPZ-6438 (Tazemetostat)2, DZNep2, UNC19993-2.4950.01259
Arginine methyltransferases
CARM1MS0493, SGC20853, TP-0643[72]-3.8120.0001381
PRMT1MS0233[72]-3.6590.0002534
PRMT6MS0233, MS049c, EPZ0204113[72], 6′-methyleneamine sinefungin3[73]-3.5210.0004301
Histone acetylation
KAT2ACPTH23[74], γ-butyrolactone3 (MB-3)[75]-4.6832.823E-06
NAA10, NAA16, NAA20, NAA38, NAA40--4.335/-3.255/-3.786/-3.801/-2.665< 0.01
NAT8, NAT9--2.573/-3.995< 0.01
NCOA5, NCOA6--3.238/-3.112< 0.002
Histone phosphorylation
BAZ1B--2.3740.01758
Histone glycosylation
OGT--3.1720.001512
1Approved for the treatment of other diseases;
2Used in clinical trials for other diseases;
3Not yet used in clinical trials;
4Activator. CRC: Colorectal cancer; OR: Objective response.
Table 2 Negative correlation between combined expression of cancer stem cell markers CD133, CD44 and CD166 and epigenetic erasers
Family/gene symbolEpidrug/chemical probeClinical trials for CRCResultsZ-scoreP value
Histone deacetylation (Zinc-dependent)
Acide valproïque1I to IIIn combination: OR in 64% patients or SD[76,77]
Belinostat2, Apicidin3
EntinostatI to I/IINo OR[78] or SD[79]
PanobinostatIPR and SD in combination with Bevacizumab[80]
Vorinostat (SAHA)I to IINo OR[81,82]; SD and PR with Bortezomib or 5FU and leucovorin or Doxorubicin[83-85]
Trichostatine A2
Mocetinostat2
Sodium phenylbutyrate2IIn combination with 5-FU: SD[86]
Class IRomidepsin (Istodax)1IIIneffective[86]
CI-994IPR in combination with carboplatin and placlitaxel[87]
HDAC8TM-2-514, CUDC-1012, Pracinostat2, Ricolinostat2, Citarinostat2, Abexinostat2, Quisinostat3, PCI-340513-2.5270.0115
Class IIa (1 catalytic site, mainly cytoplasmic)
HDAC5CUDC-1012, Pracinostat2, Domatinostat2, Quisinostat3, LMK-2353, TMP1953, TMP2693-4.1333.581E-05
Class IIb (2 catalytic sites, mainly cytoplasmic)
HDAC10CUDC-1012, CUDC-9072, Pracinostat2, Domatinostat2, Abexinostat2, Tucidinostat2, Quisinostat3-3.170.001525
Histone deacetylation NAD+ dependent (Class III)
Resveratrol4IReduced cell proliferation[88]
Salermide3[89]
SIRT6OSS_1281673-3.4670.0005257
SIRT7-2.5820.009835
Histone demethylation
LSD family of demethylases
ORY-10013, (±)-tranylcypromine3
KDM2B--3.540.0004003
KDM4D--2.7040.006848
JmjC containing lysine demethylases
JIB-043
JMJD6IOX13-2.590.00961
JMJD5IOX13-2.5880.009654
1Approved for the treatment of other diseases;
2Used in clinical trials for other diseases;
3Not yet used in clinical trials;
4Activator. CRC: Colorectal cancer; OR: Objective response; SD: Stable disease; PR: Partial response.
Table 3 Positive correlation between combined expression of cancer stem cell markers CD133, CD44 and CD166 and epigenetic erasers
Family/gene symbolPutative epidrug/chemical probeZ-scoreP value
DNA demethylation
TET2-5.9682.40E-09
Histone demethylation
LSD family of demethylases
ORY-10013, (±)-tranylcypromine3
KDM3B5.6361.74E-08
KDM4BCP23[90]5.2121.87E-07
KDM4CCP23[90]3.8959.81E-05
KDM5BCPI-4553, AS-83513, 593 (KDOAMA-253)[90]9.0929.72E-20
KDM6AGSK-J132.840.00451
KDM6BGSK-J134.0145.98E-05
1Approved for the treatment of other diseases; 2Used in clinical trials for other diseases;
3Not yet used in clinical trials.
Table 4 Positive correlation between combined expression of cancer stem cell markers CD133, CD44 and CD166 and epigenetic writers
Family/gene symbolEpidrug/chemical probeClinical trials for CRCResults/statusZ-scoreP value
Histone acetyltransferases
EP300CurcuminEarly phase I to IIILow bioavailability[91]2.5130.01198
Garcinol3, C6463
NCOA1Bufalin2[92]5.455.04E-08
NCOA4-4.1832.88E-05
NCOA7-5.7887.14E-09
KAT2BIschemin3[93]6.5147.31E-11
Activating Lysine methyltransferases
ASH1L-2.5910.009565
SMYD1-2.7390.00616
SETD7PFI-235.113.23E-07
Repressing Lysine methyltransferases
PRDM8-3.4110.0006465
Putative Lysine methyltransferase
PRDM10-2.4480.01438
Arginine methyltransferases
PRDM1-2.8740.004056
PRMT2-2.9010.003726
Histone ubiquitination
UBE2B-2.7480.005991
UBE2H-5.8096.30E-09
Histone phosphorylation
JAK1RuxolitinibPhase I and IINo benefit over Regorafenib alone[94]7.7391.01E-14
Baricitinib2, Momelotinib2, Filgotinib2, Decernotinib2, Cerdulatinib2, Solcitinib2, Oclacitinib maleate2
JAK2RuxolitinibPhase I and IINo benefit over Regorafenib alone[94]6.72.09E-11
Gandotinib2, AZD14802, BMS-9115432, AT92832, XL0192, Baricitinib2, Momelotinib2, Filgotinib2, Decernotinib2, Cerdulatinib2, JAK2/HDAC Dual Inhibitors3[95]
Histone biotinylation
BTDBiotinyl-methyl 4-(amidomethyl)benzoate3[96]4.3791.19E-05
1Approved for the treatment of other diseases;
2Used in clinical trials for other diseases;
3Not yet used in clinical trials. CRC: Colorectal cancer.
Table 5 Positive correlation between combined expression of cancer stem cell markers CD133, CD44 and CD166 and epigenetic readers
Family/gene symbolEpidrug/chemical probeZ-scoreP value
Methylated DNA binding
MBD1-2.5930.009517
MBD2-3.4770.0005076
ZBTB4-5.4963.89E-08
Methylated histone binders
Zinc finger, PHD-type
DPF33.5030.0004602
BromodomainApabetalone2, Bromosporine3
BPTF2.6210.008773
BAZ2BGSK280134.7911.66E-06
Tudor domain
TDRD1-2.4590.01394
TP53BP1-2.9650.003029
Other cofactors of epigenetic complexes
RBBP5-2.9660.003014
TADA2B-3.3820.0007189
ELP2PLX-472033.2770.00105
ELP3-2.6220.00875
TAB2-2.5510.01074
NCOR1-3.620.0002949
Chromodomain (Chromatin Organization Modifier Domain)
CHD1, CHD3, CHD9-3.007/4.099/4.367< 0.003
1Approved for the treatment of other diseases;
2Used in clinical trials for other diseases;
3Not yet used in clinical trials.
Table 6 Negative correlation between combined expression of cancer stem cell markers CD133, CD44 and CD166 and epigenetic readers
Family/gene symbolPutative epidrug/chemical probeZ-scoreP value
Methylated DNA binding
MBD3--3.6010.0003174
ZBTB38 (Kaiso family)--2.5570.01055
Histone binders
Bromodomains
BRD7BI72733, BI-95643, TP-4723[97]-4.9069.301E-07
Zinc finger, Plant Homeodomain (PHD)-type
ING1, ING5--2.544/-4.255< 0.05
PHF20--3.0940.001973
PHF14--2.9340.003344
PHF5A--2.5210.01171
DPF1--2.780.00543
Tudor domain
TDRKH--2.7550.005875
WD40 motif
EEDA-3953[98]-4.3071.652E-05
Other cofactors of epigenetic complexes
DPY30--3.5490.0003863
WDR5OICR-94293-3.310.0009321
TADA2A-2.4730.01341
1Approved for the treatment of other diseases; 2Used in clinical trials for other diseases;
3Not yet used in clinical trials.