KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM).
Journal
NAR cancer
ISSN: 2632-8674
Titre abrégé: NAR Cancer
Pays: England
ID NLM: 101769553
Informations de publication
Date de publication:
Sep 2022
Sep 2022
Historique:
received:
22
02
2022
revised:
29
06
2022
accepted:
16
07
2022
entrez:
1
8
2022
pubmed:
2
8
2022
medline:
2
8
2022
Statut:
epublish
Résumé
Malignant pleural mesothelioma (MPM) is a rare and incurable cancer, which incidence is increasing in many countries. MPM escapes the classical genetic model of cancer evolution, lacking a distinctive genetic fingerprint. Omics profiling revealed extensive heterogeneity failing to identify major vulnerabilities and restraining development of MPM-oriented therapies. Here, we performed a multilayered analysis based on a functional genome-wide CRISPR/Cas9 screening integrated with patients molecular and clinical data, to identify new non-genetic vulnerabilities of MPM. We identified a core of 18 functionally-related genes as essential for MPM cells. The chromatin reader KAP1 emerged as a dependency of MPM. We showed that KAP1 supports cell growth by orchestrating the expression of a G2/M-specific program, ensuring mitosis correct execution. Targeting KAP1 transcriptional function, by using CDK9 inhibitors resulted in a dramatic loss of MPM cells viability and shutdown of the KAP1-mediated program. Validation analysis on two independent MPM-patients sets, including a consecutive, retrospective cohort of 97 MPM, confirmed KAP1 as new non-genetic dependency of MPM and proved the association of its dependent gene program with reduced patients' survival probability. Overall these data: provided new insights into the biology of MPM delineating KAP1 and its target genes as building blocks of its clinical aggressiveness.
Identifiants
pubmed: 35910692
doi: 10.1093/narcan/zcac024
pii: zcac024
pmc: PMC9336180
doi:
Types de publication
Journal Article
Langues
eng
Pagination
zcac024Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.
Références
J Mol Biol. 2000 Feb 4;295(5):1139-62
pubmed: 10653693
Mol Cell. 2016 Jan 7;61(1):39-53
pubmed: 26725010
J Biol Chem. 2011 Jul 29;286(30):26267-76
pubmed: 21652716
Cell Mol Life Sci. 2021 Jul;78(14):5543-5567
pubmed: 34146121
Mol Cancer Res. 2020 Jan;18(1):140-152
pubmed: 31624086
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Cancer Res. 2009 Dec 1;69(23):9073-82
pubmed: 19887624
Clin Cancer Res. 2020 Jan 15;26(2):373-383
pubmed: 31645353
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23588-23596
pubmed: 32900933
Bioinformatics. 2009 Apr 15;25(8):1091-3
pubmed: 19237447
Carcinogenesis. 2008 Aug;29(8):1555-9
pubmed: 18310086
Nat Rev Cancer. 2017 Jul 25;17(8):475-488
pubmed: 28740119
J Biomed Sci. 2017 Aug 29;24(1):63
pubmed: 28851455
Genes Dev. 2002 Apr 15;16(8):919-32
pubmed: 11959841
J Clin Med. 2021 Jun 02;10(11):
pubmed: 34199544
Genome Biol. 2014;15(12):550
pubmed: 25516281
Oncogene. 2010 Apr 22;29(16):2325-36
pubmed: 20101221
Mol Cancer Ther. 2016 Oct;15(10):2498-2507
pubmed: 27507853
Sci Signal. 2018 Aug 14;11(543):
pubmed: 30108183
Mol Clin Oncol. 2022 Apr;16(4):89
pubmed: 35251640
Thyroid. 2021 Feb;31(2):247-263
pubmed: 32495722
Mod Pathol. 2010 Apr;23(4):531-8
pubmed: 20081810
Oncogene. 2019 Oct;38(42):6801-6817
pubmed: 31406246
Nucleic Acids Res. 2016 Jan 8;44(1):164-74
pubmed: 26384566
Nat Commun. 2019 Mar 22;10(1):1333
pubmed: 30902996
J Thorac Oncol. 2016 Feb;11(2):142-54
pubmed: 26811225
Mol Cell. 2020 Jun 18;78(6):1133-1151.e14
pubmed: 32402252
Mol Cell Biol. 2011 May;31(9):1833-47
pubmed: 21343339
Clin Cancer Res. 2020 Feb 15;26(4):922-934
pubmed: 31699827
Nat Genet. 2016 Apr;48(4):407-16
pubmed: 26928227
Oncogene. 2012 Dec 6;31(49):5117-22
pubmed: 22286761
Nat Commun. 2021 Mar 19;12(1):1751
pubmed: 33741915
Nucleic Acids Res. 2012 Feb;40(4):1561-78
pubmed: 22064854
Nat Genet. 2007 Dec;39(12):1507-11
pubmed: 17994021
EMBO Rep. 2018 Oct;19(10):
pubmed: 30061100
J Immunol. 2011 Nov 1;187(9):4754-63
pubmed: 21940674
Front Genet. 2020 Aug 07;11:899
pubmed: 32849853
Nat Protoc. 2006;1(3):1458-61
pubmed: 17406435
J Thorac Cardiovasc Surg. 2020 Apr;159(4):1584-1593.e2
pubmed: 31590954
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Trends Biochem Sci. 2013 Dec;38(12):603-11
pubmed: 24120742
Genom Data. 2016 Feb 04;7:250-5
pubmed: 26981421
Cell. 2017 Feb 9;168(4):629-643
pubmed: 28187285
Ind Health. 2007 Jun;45(3):379-87
pubmed: 17634686
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Mol Cell. 2007 Dec 14;28(5):823-37
pubmed: 18082607
Cancer Res. 2015 Jan 15;75(2):264-9
pubmed: 25488749
Cancer Discov. 2018 Dec;8(12):1548-1565
pubmed: 30322867
PLoS One. 2009;4(2):e4404
pubmed: 19198660
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Cancers (Basel). 2021 May 01;13(9):
pubmed: 34062779
J Cell Physiol. 2012 Jan;227(1):44-58
pubmed: 21412769
High Throughput. 2018 Jul 27;7(3):
pubmed: 30060501
Genome Med. 2021 Jul 14;13(1):113
pubmed: 34261524
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
J Thorac Oncol. 2016 Oct;11(10):1615-26
pubmed: 27282309
Nat Med. 2019 Mar;25(3):403-418
pubmed: 30842676
Mol Cancer. 2021 Apr 6;20(1):63
pubmed: 33823854