RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer.
CP: Cancer
DNMT inhibitors
RNA mis-splicing
SETD2
ccRCC
viral mimicry
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
31 01 2023
31 01 2023
Historique:
received:
19
05
2022
revised:
26
10
2022
accepted:
05
01
2023
pubmed:
21
1
2023
medline:
7
2
2023
entrez:
20
1
2023
Statut:
ppublish
Résumé
Tumors with mutations in chromatin regulators present attractive targets for DNA hypomethylating agent 5-aza-2'-deoxycytidine (DAC) therapy, which further disrupts cancer cells' epigenomic fidelity and reactivates transposable element (TE) expression to drive viral mimicry responses. SETD2 encodes a histone methyltransferase (H3K36me3) and is prevalently mutated in advanced kidney cancers. Here, we show that SETD2-mutant kidney cancer cells are especially sensitive in vitro and in vivo to DAC treatment. We find that the viral mimicry response are direct consequences of mis-splicing events, such as exon inclusions or extensions, triggered by DAC treatment in an SETD2-loss context. Comprehensive epigenomic analysis reveals H3K9me3 deposition, rather than DNA methylation dynamics, across intronic TEs might contribute to elevated mis-splicing rates. Through epigenomic and transcriptomic analyses, we show that SETD2-deficient kidney cancers are prone to mis-splicing, which can be therapeutically exacerbated with DAC treatment to increase viral mimicry activation and provide synergy with combinatorial immunotherapy approaches.
Identifiants
pubmed: 36662621
pii: S2211-1247(23)00027-X
doi: 10.1016/j.celrep.2023.112016
pmc: PMC10034851
mid: NIHMS1870545
pii:
doi:
Substances chimiques
Histones
0
Chromatin
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
112016Subventions
Organisme : NCI NIH HHS
ID : P30 CA014089
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA209859
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA243878
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests P.A.J. is a consultant for Zymo Research Corporation, and G.L. is a consultant for Pangea Laboratory.
Références
Science. 2010 Feb 19;327(5968):996-1000
pubmed: 20133523
Nucleic Acids Res. 2018 Nov 16;46(20):e123
pubmed: 30085201
Nat Rev Nephrol. 2020 Aug;16(8):435-451
pubmed: 32561872
Nat Struct Mol Biol. 2011 Mar;18(3):337-44
pubmed: 21358630
Genome Res. 2018 Aug;28(8):1147-1157
pubmed: 29970451
Cancer Cell. 2021 Nov 8;39(11):1497-1518.e11
pubmed: 34715028
Nat Rev Cancer. 2011 Sep 23;11(10):726-34
pubmed: 21941284
Cell. 2013 Aug 1;154(3):541-55
pubmed: 23871696
Genome Biol. 2011 Aug 22;12(8):R82
pubmed: 21859475
Nat Struct Mol Biol. 2011 Jul 26;18(9):977-83
pubmed: 21792193
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Sci Rep. 2015 Apr 08;5:9465
pubmed: 25853938
Cancer Cell. 2017 Aug 14;32(2):221-237.e13
pubmed: 28781121
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Cell. 2017 Jul 27;170(3):492-506.e14
pubmed: 28753426
Science. 2014 Jan 3;343(6166):84-87
pubmed: 24336571
Blood. 2017 Dec 14;130(24):2576-2578
pubmed: 29242204
Eur Urol. 2017 Mar;71(3):405-414
pubmed: 27751729
Cell. 2016 Aug 11;166(4):950-962
pubmed: 27518565
J Clin Invest. 2018 Nov 1;128(11):4804-4820
pubmed: 30137025
Lancet. 2009 Mar 28;373(9669):1119-32
pubmed: 19269025
Nucleic Acids Res. 2019 Jul 2;47(W1):W158-W165
pubmed: 31165883
Mod Pathol. 2016 Jan;29(1):34-42
pubmed: 26516698
PLoS Comput Biol. 2017 Nov 27;13(11):e1005851
pubmed: 29176847
Nat Biotechnol. 2019 Aug;37(8):907-915
pubmed: 31375807
Int J Mol Sci. 2019 Feb 27;20(5):
pubmed: 30818762
Oncogene. 2020 Feb;39(7):1543-1556
pubmed: 31685946
Cell. 2013 Apr 25;153(3):590-600
pubmed: 23622243
Nat Commun. 2021 Nov 8;12(1):6452
pubmed: 34750379
Nat Genet. 2016 Apr;48(4):407-16
pubmed: 26928227
Nat Commun. 2021 Mar 4;12(1):1443
pubmed: 33664260
Carcinogenesis. 2010 Jan;31(1):27-36
pubmed: 19752007
Cell. 2018 Apr 19;173(3):595-610.e11
pubmed: 29656894
Nat Biotechnol. 2015 Mar;33(3):290-5
pubmed: 25690850
Cell. 2021 Jul 22;184(15):4032-4047.e31
pubmed: 34171309
Cell Rep. 2018 Apr 3;23(1):313-326.e5
pubmed: 29617669
Immunity. 2021 May 11;54(5):875-884
pubmed: 33979585
PLoS Comput Biol. 2018 Aug 17;14(8):e1006360
pubmed: 30118475
Cancer Res. 2008 Jun 15;68(12):4709-18
pubmed: 18559517
Elife. 2014 May 06;3:e02482
pubmed: 24843002
Clin Genitourin Cancer. 2021 Aug;19(4):339-345
pubmed: 33839039
JCI Insight. 2020 Jun 4;5(11):
pubmed: 32493845
JCI Insight. 2018 Aug 23;3(16):
pubmed: 30135306
Cell Death Dis. 2020 Jan 27;11(1):69
pubmed: 31988284
Clin Cancer Res. 2013 Jan 1;19(1):128-37
pubmed: 23155185
Cancer Cell. 2020 Sep 14;38(3):350-365.e7
pubmed: 32619406
J Clin Invest. 2017 Sep 1;127(9):3375-3391
pubmed: 28825595
Cell. 2018 Apr 19;173(3):581-594.e12
pubmed: 29656895
Genome Biol. 2021 May 10;22(1):147
pubmed: 33971937
Hepatology. 2018 Oct;68(4):1412-1428
pubmed: 29774579
Oncotarget. 2015 Feb 28;6(6):4066-79
pubmed: 25714014
Oncogene. 2016 Mar 24;35(12):1565-74
pubmed: 26073078
Cancer Cell. 2012 May 15;21(5):655-667
pubmed: 22624715
Eur Urol. 2013 May;63(5):848-54
pubmed: 23036577
Nat Commun. 2020 Nov 3;11(1):5387
pubmed: 33144593
Nat Rev Genet. 2016 Sep 15;17(10):630-41
pubmed: 27629931
F1000Res. 2020 Apr 28;9:304
pubmed: 32489650
BMC Cancer. 2009 Aug 21;9:290
pubmed: 19698110
Cell. 2015 Aug 27;162(5):961-73
pubmed: 26317465
Nat Rev Urol. 2018 Oct;15(10):599-614
pubmed: 30030490
Nat Genet. 2009 Mar;41(3):376-81
pubmed: 19182803
Nat Rev Cancer. 2019 Mar;19(3):151-161
pubmed: 30723290
Cell. 2022 Feb 3;185(3):563-575.e11
pubmed: 35120664
Biophys Rep. 2018;4(4):170-177
pubmed: 30310854
Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):10238-44
pubmed: 27573823
Sci Rep. 2016 Apr 19;6:24545
pubmed: 27090213
Gut. 2016 Dec;65(12):1960-1972
pubmed: 26338826
Nat Commun. 2016 Apr 28;7:11453
pubmed: 27121154
Neoplasia. 2019 Feb;21(2):247-256
pubmed: 30660076
Eur Urol Focus. 2017 Oct;3(4-5):421-427
pubmed: 28753773
Oncotarget. 2016 Jan 12;7(2):1927-46
pubmed: 26646321
Nature. 2017 Mar 2;543(7643):72-77
pubmed: 28225755
Nat Genet. 2019 May;51(5):844-856
pubmed: 31040401
Nature. 2020 Dec;588(7836):169-173
pubmed: 33087935
Nature. 2015 Apr 9;520(7546):243-7
pubmed: 25607372
Bioinformatics. 2017 Feb 15;33(4):558-560
pubmed: 28035024
Cell. 2021 Jan 21;184(2):352-369.e23
pubmed: 33357448
Cell. 2021 Jan 21;184(2):384-403.e21
pubmed: 33450205
Cancer Cell. 2014 Oct 13;26(4):577-90
pubmed: 25263941
FEBS J. 2022 Mar;289(5):1160-1179
pubmed: 33471418
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Bioinformatics. 2015 Nov 15;31(22):3593-9
pubmed: 26206304
Cell. 2015 Aug 27;162(5):974-86
pubmed: 26317466
Nat Rev Urol. 2014 Sep;11(9):517-25
pubmed: 25112856