VRK1 Is a Synthetic-Lethal Target in VRK2-Deficient Glioblastoma.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
02 11 2022
02 11 2022
Historique:
received:
31
12
2021
revised:
15
07
2022
accepted:
01
09
2022
pubmed:
8
9
2022
medline:
4
11
2022
entrez:
7
9
2022
Statut:
ppublish
Résumé
Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic-lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2-M arrest and DNA damage. The VRK1-VRK2 synthetic-lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line-derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM. A paralog synthetic-lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease.
Identifiants
pubmed: 36069976
pii: 709959
doi: 10.1158/0008-5472.CAN-21-4443
pmc: PMC9627132
doi:
Substances chimiques
VRK1 protein, human
EC 2.7.11.1
VRK2 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4044-4057Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
Références
Cell Mol Life Sci. 2018 Jul;75(14):2591-2611
pubmed: 29340707
Cancer Discov. 2016 Apr;6(4):430-45
pubmed: 26603525
Cancers (Basel). 2020 Nov 20;12(11):
pubmed: 33233777
Cell. 2013 Oct 10;155(2):462-77
pubmed: 24120142
PLoS One. 2008 Feb 20;3(2):e1642
pubmed: 18286197
Sci Rep. 2022 Jul 1;12(1):11210
pubmed: 35778595
Nat Genet. 2017 Dec;49(12):1779-1784
pubmed: 29083409
Histol Histopathol. 2009 Jun;24(6):749-59
pubmed: 19337973
Cancer Lett. 2021 Apr 10;503:117-128
pubmed: 33516791
Nat Commun. 2021 Mar 12;12(1):1661
pubmed: 33712601
Cell Rep. 2020 Dec 15;33(11):108493
pubmed: 33326793
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8997-9002
pubmed: 10908652
Science. 1997 Nov 7;278(5340):1064-8
pubmed: 9353181
Mol Biol Cell. 2006 May;17(5):2451-64
pubmed: 16495336
Curr Opin Cell Biol. 2015 Jun;34:61-8
pubmed: 26072104
Cell Signal. 2011 Aug;23(8):1267-72
pubmed: 21514377
J Cell Sci. 2008 Sep 15;121(Pt 18):3035-41
pubmed: 18713830
Cancer Res. 2021 Aug 1;81(15):3971-3984
pubmed: 34099491
J Cell Sci. 2003 Sep 15;116(Pt 18):3811-23
pubmed: 12902403
Cancer Cell. 2006 May;9(5):391-403
pubmed: 16697959
Sci Rep. 2019 Sep 16;9(1):13381
pubmed: 31527692
JAMA Neurol. 2013 Dec;70(12):1491-8
pubmed: 24126608
Nat Rev Drug Discov. 2020 Jan;19(1):23-38
pubmed: 31712683
Cancer Cell. 2021 Jun 14;39(6):827-844.e10
pubmed: 34129824
Science. 2020 Aug 14;369(6505):823-828
pubmed: 32792394
Cancer Discov. 2021 Sep;11(9):2282-2299
pubmed: 33883167
Science. 2008 Sep 26;321(5897):1807-12
pubmed: 18772396
Mol Biol Cell. 2017 Aug 15;28(17):2241-2250
pubmed: 28637768
Lancet Oncol. 2009 May;10(5):459-66
pubmed: 19269895
Nature. 2019 Apr;568(7753):551-556
pubmed: 30971823
EuPA Open Proteom. 2015 Jun;7:11-19
pubmed: 25821719
Mol Cancer Res. 2006 Mar;4(3):177-85
pubmed: 16547155
Neurology. 2016 Jul 5;87(1):65-70
pubmed: 27281532
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3290-5
pubmed: 15728376
ACS Med Chem Lett. 2019 Aug 19;10(9):1266-1271
pubmed: 31531195
Trends Biochem Sci. 2017 Mar;42(3):193-205
pubmed: 28202332
Biomed Pharmacother. 2017 May;89:1086-1091
pubmed: 28298069
JAMA Oncol. 2021 May 1;7(5):675-676
pubmed: 33475680
Mol Biol Cell. 2014 Mar;25(6):891-903
pubmed: 24430874
Sci Rep. 2017 Aug 8;7(1):7501
pubmed: 28790404
Am J Hum Genet. 2011 May 13;88(5):650-6
pubmed: 21549337
Cell. 1990 May 18;61(4):579-89
pubmed: 2344612
Pathol Res Pract. 2018 Jan;214(1):112-118
pubmed: 29103766
Nat Rev Cancer. 2005 Sep;5(9):689-98
pubmed: 16110319
Mol Cell Biol. 2004 Dec;24(23):10366-80
pubmed: 15542844
PLoS One. 2011;6(9):e24807
pubmed: 21961046
Am J Hum Genet. 2009 Aug;85(2):281-9
pubmed: 19646678
Nucleus. 2018 Dec 31;9(1):368-379
pubmed: 29936894
Cancer Treat Rev. 2019 Nov;80:101896
pubmed: 31541850
Int J Mol Sci. 2021 Jan 18;22(2):
pubmed: 33477674
Oncol Lett. 2020 Aug;20(2):1163-1170
pubmed: 32724356
EMBO J. 2007 Jan 10;26(1):132-43
pubmed: 17170708
Sci Rep. 2018 Jul 26;8(1):11265
pubmed: 30050127
Cell Death Dis. 2013 Feb 28;4:e513
pubmed: 23449449
FEBS J. 2006 Jun;273(11):2487-504
pubmed: 16704422
Mol Cell Biol. 2007 Dec;27(24):8533-46
pubmed: 17938195
Acta Neuropathol. 2016 Jun;131(6):803-20
pubmed: 27157931
Cell. 2017 Aug 24;170(5):956-972.e23
pubmed: 28841419
N Engl J Med. 2015 Jun 25;372(26):2481-98
pubmed: 26061751
Mol Biol Cell. 2013 Feb;24(3):373-84
pubmed: 23223570
Front Cell Dev Biol. 2021 Jun 14;9:683038
pubmed: 34195200
Genes Dev. 2015 Jun 15;29(12):1203-17
pubmed: 26109046