A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
22
12
2021
accepted:
06
08
2022
revised:
01
09
2022
pubmed:
23
8
2022
medline:
9
9
2022
entrez:
22
8
2022
Statut:
epublish
Résumé
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.
Identifiants
pubmed: 35994477
doi: 10.1371/journal.pgen.1010376
pii: PGENETICS-D-21-01659
pmc: PMC9436093
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Protein Isoforms
0
Histone Deacetylase 1
EC 3.5.1.98
Histone Deacetylase 2
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010376Subventions
Organisme : NHGRI NIH HHS
ID : R21 HG011520
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Biochim Biophys Acta. 2015 Aug;1853(8):1818-26
pubmed: 25920810
Clin Cancer Res. 2008 Mar 15;14(6):1669-77
pubmed: 18347167
Bioorg Med Chem Lett. 2007 Aug 15;17(16):4619-24
pubmed: 17555962
J Hematol Oncol. 2016 Jan 12;9:3
pubmed: 26759222
Front Genet. 2020 Sep 11;11:578011
pubmed: 33024443
J Biol Chem. 1999 Aug 20;274(34):23977-90
pubmed: 10446166
Cold Spring Harb Perspect Med. 2016 Oct 3;6(10):
pubmed: 27599530
Oncotarget. 2015 Mar 10;6(7):4863-87
pubmed: 25605023
Trends Pharmacol Sci. 2017 Apr;38(4):363-377
pubmed: 28139258
Mol Cancer Ther. 2016 May;15(5):830-41
pubmed: 26809490
Mol Cell Biol. 2005 Sep;25(17):7711-24
pubmed: 16107717
Nat Commun. 2018 Jan 4;9(1):53
pubmed: 29302039
Expert Rev Anticancer Ther. 2010 Jun;10(6):935-54
pubmed: 20553216
Blood. 2013 Feb 21;121(8):1335-44
pubmed: 23287868
Neuron. 2001 Aug 16;31(3):353-65
pubmed: 11516394
FEBS J. 2016 Nov;283(22):4032-4046
pubmed: 27112360
Mol Cell Biol. 2015 Nov 23;36(3):462-74
pubmed: 26598605
Front Oncol. 2021 Sep 16;11:723966
pubmed: 34604061
J Biol Chem. 2014 Jul 11;289(28):19519-30
pubmed: 24821725
Nat Methods. 2013 Oct;10(10):965-71
pubmed: 24161985
ACS Chem Biol. 2016 Oct 21;11(10):2685-2692
pubmed: 27459069
Cell. 2009 Sep 4;138(5):1019-31
pubmed: 19698979
Leuk Lymphoma. 2020 Feb;61(2):309-317
pubmed: 31617432
Nature. 2011 Aug 24;477(7364):340-3
pubmed: 21866103
Dev Cell. 2010 Dec 14;19(6):807-18
pubmed: 21093383
Genes Dev. 2010 Mar 1;24(5):455-69
pubmed: 20194438
Biochim Biophys Acta. 1996 Sep 5;1296(2):181-8
pubmed: 8814225
Clin Cancer Res. 2009 Jan 1;15(1):91-9
pubmed: 19118036
Nature. 1997 Sep 25;389(6649):349-52
pubmed: 9311776
Cancer Biol Ther. 2012 May;13(7):567-74
pubmed: 22406992
Epigenetics Chromatin. 2013 Aug 15;6(1):27
pubmed: 23947532
Br J Cancer. 2019 Mar;120(6):658-667
pubmed: 30765872
J Mol Biol. 2001 Apr 20;308(1):27-38
pubmed: 11302704
Expert Opin Ther Targets. 2013 Jan;17(1):29-41
pubmed: 23062071
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7751-5
pubmed: 19416910
PLoS One. 2021 Sep 17;16(9):e0253756
pubmed: 34534222
Proc Natl Acad Sci U S A. 2010 May 4;107(18):8242-7
pubmed: 20404188
Tumour Biol. 2016 Sep;37(9):11535-11540
pubmed: 27209410
Chromosoma. 2014 Mar;123(1-2):67-78
pubmed: 24170248
Clin Cancer Res. 2015 Sep 15;21(18):4097-109
pubmed: 25878331
Oncotarget. 2015 Oct 13;6(31):31134-50
pubmed: 26429859
J Biol Chem. 2003 Jul 4;278(27):24858-64
pubmed: 12716897
Nat Methods. 2020 Apr;17(4):399-404
pubmed: 32203386
Cell Death Differ. 2016 Jul;23(7):1119-27
pubmed: 27082454
Blood. 2017 Dec 7;130(23):2499-2503
pubmed: 28972014
Blood. 2013 Mar 14;121(11):2038-50
pubmed: 23327920
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Virol. 2004 Apr;78(8):3851-62
pubmed: 15047801
Front Oncol. 2015 Aug 24;5:189
pubmed: 26380220
Transl Oncol. 2022 Jul;21:101426
pubmed: 35460943
Nat Commun. 2019 Mar 5;10(1):1055
pubmed: 30837475
Oral Oncol. 2018 Nov;86:105-112
pubmed: 30409290
Nat Methods. 2016 Jul;13(7):577-80
pubmed: 27240256
Mol Cell Biol. 2003 Aug;23(15):5122-31
pubmed: 12861000
Science. 2015 Nov 27;350(6264):1092-6
pubmed: 26472760
Int J Mol Sci. 2021 Aug 24;22(17):
pubmed: 34502048
Nat Commun. 2020 Feb 7;11(1):796
pubmed: 32034158
J Virol. 2008 Nov;82(22):11283-93
pubmed: 18799579
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11187-92
pubmed: 9736711
Cancer Lett. 2009 May 8;277(1):8-21
pubmed: 18824292
Development. 2014 Feb;141(3):604-616
pubmed: 24449838
EMBO J. 2013 Dec 11;32(24):3176-91
pubmed: 24240174
Prostate. 2004 May 1;59(2):177-89
pubmed: 15042618
Nature. 1995 Oct 5;377(6548):397-404
pubmed: 7566114
Cells. 2019 Nov 13;8(11):
pubmed: 31766144
J Biol Chem. 2006 Dec 29;281(52):40292-301
pubmed: 17065153
Nat Med. 2007 Mar;13(3):324-31
pubmed: 17322895
Mol Cell. 2002 Jan;9(1):45-57
pubmed: 11804585
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9873-8
pubmed: 10449787
Mol Cell Biol. 2007 Nov;27(21):7641-8
pubmed: 17724083
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15064-9
pubmed: 15477595
Biochim Biophys Acta. 1999 Dec 23;1489(2-3):365-73
pubmed: 10673037
Science. 2009 Aug 14;325(5942):834-40
pubmed: 19608861
Mol Cancer Res. 2021 Jan;19(1):3-13
pubmed: 32605929
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Cell Death Dis. 2018 Mar 14;9(3):398
pubmed: 29540666
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):E5335-E5342
pubmed: 28630323
Mol Cell. 2013 Dec 26;52(6):769-82
pubmed: 24268577
Biochem Soc Trans. 2013 Jun;41(3):741-9
pubmed: 23697933
FEBS Lett. 1998 Jan 9;421(2):109-14
pubmed: 9468289
Mol Cell Biol. 2006 Jul;26(14):5259-69
pubmed: 16809764
J Biol Chem. 2011 Jan 21;286(3):1850-9
pubmed: 21078666
Genes Dev. 2007 Jul 15;21(14):1790-802
pubmed: 17639084
Nat Struct Mol Biol. 2013 Sep;20(9):1040-6
pubmed: 23934153
BMC Cancer. 2013 Apr 30;13:215
pubmed: 23627572
Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):8608-8613
pubmed: 28739911
Cell Mol Life Sci. 2012 Jul;69(13):2173-87
pubmed: 22286122
BMC Clin Pathol. 2014 Mar 13;14(1):10
pubmed: 24624923
Lancet Oncol. 2008 Feb;9(2):139-48
pubmed: 18207460
Mol Cell Biol. 2007 Feb;27(4):1280-95
pubmed: 17158926
Biostatistics. 2017 Apr 1;18(2):275-294
pubmed: 27756721
Genes Dev. 2009 Jul 15;23(14):1625-30
pubmed: 19605684
Mol Cell. 2008 Apr 11;30(1):61-72
pubmed: 18406327
Adv Exp Med Biol. 2020;1257:75-83
pubmed: 32483732
Cancer Cell. 2010 Nov 16;18(5):436-47
pubmed: 21075309
Nat Protoc. 2007;2(8):1896-906
pubmed: 17703201
Oncoimmunology. 2014 Jan 1;3(1):e27414
pubmed: 24701376
Dev Dyn. 2008 Aug;237(8):2256-67
pubmed: 18651664
J Biol Chem. 2001 Sep 21;276(38):35826-35
pubmed: 11466315
Nature. 1995 Oct 5;377(6548):454-7
pubmed: 7566127
Cancer Res. 2007 Oct 1;67(19):9047-54
pubmed: 17909008
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Biochem Biophys Res Commun. 2003 Oct 17;310(2):529-36
pubmed: 14521942
Cancer Biol Ther. 2014 Jun 1;15(6):655-64
pubmed: 24618703
Nucleic Acids Res. 2016 Dec 1;44(21):10017-10030
pubmed: 27738139
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Biol Open. 2013 Aug 22;2(10):1070-7
pubmed: 24167717
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
EMBO J. 2002 Jun 3;21(11):2672-81
pubmed: 12032080
Br J Cancer. 2016 Mar 15;114(6):605-11
pubmed: 26908329
Am J Clin Exp Urol. 2015 Apr 25;3(1):13-23
pubmed: 26069883
J Med Chem. 2020 Nov 12;63(21):12460-12484
pubmed: 32608981
Nature. 2009 May 7;459(7243):55-60
pubmed: 19424149
Int J Oncol. 2007 Jul;31(1):219-23
pubmed: 17549425
Cell Chem Biol. 2022 Jul 21;29(7):1140-1152.e5
pubmed: 35298895
Leukemia. 2019 Jun;33(6):1400-1410
pubmed: 30622285
Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9840-5
pubmed: 24958871
Mol Cell Proteomics. 2018 Jun;17(6):1239-1244
pubmed: 29487113
Leukemia. 2006 Mar;20(3):437-43
pubmed: 16424870
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Biopolymers. 2013 Feb;99(2):112-26
pubmed: 23175386
Nucleic Acids Res. 2015 Feb 27;43(4):2033-44
pubmed: 25653165
Genes Dev. 2015 Oct 15;29(20):2123-39
pubmed: 26494788
Bioinformatics. 2010 Apr 1;26(7):966-8
pubmed: 20147306
Mol Cell Biol. 2006 Nov;26(21):7913-28
pubmed: 16940178
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7876-81
pubmed: 19380719
J Clin Invest. 2008 Nov;118(11):3588-97
pubmed: 18830415
Mol Cell Proteomics. 2017 May;16(5):873-890
pubmed: 28325852
J Cell Physiol. 2014 Nov;229(11):1571-4
pubmed: 24633655
FEBS Lett. 2004 Apr 23;564(1-2):171-6
pubmed: 15094062
Cold Spring Harb Perspect Biol. 2016 Apr 01;8(4):a019521
pubmed: 27037415
Blood. 2006 Nov 15;108(10):3271-9
pubmed: 16882711
Nat Biotechnol. 2015 Apr;33(4):415-23
pubmed: 25751058
Expert Opin Investig Drugs. 2017 Aug;26(8):965-971
pubmed: 28718331
Nucleic Acids Res. 2021 May 21;49(9):5106-5123
pubmed: 33939832
Lancet Haematol. 2017 Dec;4(12):e595-e606
pubmed: 29153976
Nat Neurosci. 2013 Aug;16(8):1008-15
pubmed: 23852118
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3519-24
pubmed: 9520398
EMBO J. 2006 Sep 6;25(17):3966-74
pubmed: 16917504
Nucleic Acids Res. 2008 Jan;36(1):121-32
pubmed: 17999998
Neuroepigenetics. 2015 Jan 1;1:34-40
pubmed: 25705589
Int J Cancer. 2015 Mar 1;136(5):E207-18
pubmed: 25082736
Genes Dev. 1999 Feb 15;13(4):412-23
pubmed: 10049357
Biochim Biophys Acta. 2016 Oct;1864(10):1372-401
pubmed: 27296530
Epigenetics. 2018;13(5):519-535
pubmed: 29940793
Biochim Biophys Acta. 2009 Jan;1789(1):37-44
pubmed: 18675384
Nat Struct Mol Biol. 2004 Apr;11(4):308-15
pubmed: 15004546
J Biol Chem. 2002 Dec 13;277(50):48043-50
pubmed: 12376548
Mol Immunol. 2010 Nov-Dec;48(1-3):248-56
pubmed: 20817300
Front Oncol. 2021 Aug 26;11:735940
pubmed: 34513712
J Biol Chem. 2002 Mar 15;277(11):9447-54
pubmed: 11779848
Haematologica. 2020 Jan;105(1):e26-e28
pubmed: 31073068
Genes Dev. 2002 Mar 15;16(6):687-92
pubmed: 11914274
Cell Cycle. 2010 Nov 15;9(22):4477-86
pubmed: 21088488
J Biol Chem. 2006 Nov 17;281(46):35070-80
pubmed: 16980305
Clin Epigenetics. 2016 Jul 22;8:79
pubmed: 27453763
Cancers (Basel). 2019 Nov 14;11(11):
pubmed: 31739588
Mol Cell Biol. 2014 Jul;34(14):2760-70
pubmed: 24820421
EMBO J. 2000 Aug 15;19(16):4342-50
pubmed: 10944117