Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer.
RNA processing
gene expression
mitochondria
prostate cancer susceptibility
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 06 2023
07 06 2023
Historique:
revised:
30
03
2023
received:
20
01
2023
accepted:
31
03
2023
medline:
8
6
2023
pubmed:
24
4
2023
entrez:
24
04
2023
Statut:
ppublish
Résumé
Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking. We used CRISPR-Cas9 genome editing to introduce a missense variant identified in the ELAC2 gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouse Elac2 gene as well as to generate a prostate-specific knockout of Elac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer. Multiomic profiling revealed defects in energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired noncoding RNA processing and reduced protein synthesis. Our physiologically relevant models show that the ELAC2 variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer.
Identifiants
pubmed: 37093546
doi: 10.15252/emmm.202317463
pmc: PMC10245041
doi:
Banques de données
GEO
['GSE201184']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e17463Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Nucleic Acids Res. 2019 Jan 8;47(D1):D155-D162
pubmed: 30423142
Mol Endocrinol. 1994 Feb;8(2):230-9
pubmed: 8170479
Bioinformatics. 2018 Apr 1;34(7):1116-1124
pubmed: 29228294
Nat Rev Cancer. 2007 Apr;7(4):281-94
pubmed: 17384583
Sci Adv. 2019 Dec 20;5(12):eaay2118
pubmed: 31903419
Nucleic Acids Res. 2003 May 1;31(9):2272-8
pubmed: 12711671
Am J Hum Genet. 2013 Aug 8;93(2):211-23
pubmed: 23849775
Am J Hum Genet. 2000 Oct;67(4):1014-9
pubmed: 10986046
PLoS One. 2017 Oct 26;12(10):e0185056
pubmed: 29073143
Nature. 1998 Mar 12;392(6672):190-3
pubmed: 9515965
Cell Metab. 2020 May 5;31(5):987-1003.e8
pubmed: 32315597
J Cell Physiol. 2017 Jan;232(1):14-8
pubmed: 26992144
Nucleic Acids Res. 2019 Jan 8;47(D1):D801-D806
pubmed: 30407599
Trends Endocrinol Metab. 2017 Aug;28(8):587-596
pubmed: 28622965
J Cancer Res Clin Oncol. 1996;122(3):135-40
pubmed: 8601560
RNA Biol. 2011 Jul-Aug;8(4):616-26
pubmed: 21593607
Dig Dis Sci. 2014 May;59(5):895-6
pubmed: 24595655
Cancer Res. 2001 Sep 1;61(17):6494-9
pubmed: 11522646
Front Cell Dev Biol. 2022 Jan 21;9:723466
pubmed: 35127694
Int J Cancer. 2003 Jan 20;103(3):306-15
pubmed: 12471613
Sci Signal. 2015 Nov 17;8(403):ra116
pubmed: 26577921
Am J Hum Genet. 2002 Dec;71(6):1475-8
pubmed: 12515253
Oncogene. 2021 Feb;40(7):1362-1374
pubmed: 33420365
Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R103-21
pubmed: 14749351
Front Pharmacol. 2014 May 28;5:118
pubmed: 24904421
Nat Rev Urol. 2021 Apr;18(4):209-226
pubmed: 33742189
Genome Biol. 2014 Feb 10;15(2):R34
pubmed: 24512684
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nucleic Acids Res. 2012 Jan;40(1):37-52
pubmed: 21911355
Cell Signal. 2015 Mar;27(3):510-8
pubmed: 25578861
Nature. 2010 Aug 12;466(7308):869-73
pubmed: 20668451
Bioinformatics. 2019 Jun 1;35(12):2084-2092
pubmed: 30395178
Nat Rev Dis Primers. 2021 Feb 4;7(1):9
pubmed: 33542230
Adv Exp Med Biol. 2019;1210:319-331
pubmed: 31900915
Exp Mol Med. 2015 Aug 07;47:e176
pubmed: 26251261
Elife. 2021 Jan 21;10:
pubmed: 33476259
Nat Struct Mol Biol. 2021 Sep;28(9):713-723
pubmed: 34489609
BJU Int. 2005 Dec;96(9):1380-5
pubmed: 16287462
Clin Cancer Res. 1998 Apr;4(4):963-71
pubmed: 9563891
Oncogene. 2016 Sep 8;35(36):4675-88
pubmed: 26829052
Int J Cancer. 2003 Apr 10;104(3):283-8
pubmed: 12569551
J Cell Biol. 1991 Oct;115(2):517-33
pubmed: 1918152
PLoS Genet. 2015 Mar 27;11(3):e1005089
pubmed: 25816300
Nat Genet. 2001 Feb;27(2):172-80
pubmed: 11175785
Nat Cell Biol. 2018 Oct;20(10):1145-1158
pubmed: 30250064
EMBO Mol Med. 2023 Jun 7;15(6):e17463
pubmed: 37093546
Cell Rep. 2018 Apr 3;23(1):127-142
pubmed: 29617655
Mol Metab. 2019 Feb;20:1-13
pubmed: 30553771
Gigascience. 2021 Feb 16;10(2):
pubmed: 33590861
Clin Sci (Lond). 2015 Jun;128(12):863-75
pubmed: 25818486
Nat Genet. 2002 Feb;30(2):181-4
pubmed: 11799394
FEBS Open Bio. 2020 Apr;10(4):674-688
pubmed: 32027093
Cell. 2008 Oct 31;135(3):462-74
pubmed: 18984158
EMBO Mol Med. 2012 Mar;4(3):143-59
pubmed: 22351564
Oncol Lett. 2018 Nov;16(5):6663-6669
pubmed: 30405806
Nat Commun. 2021 Jul 9;12(1):4227
pubmed: 34244482
PLoS One. 2011;6(7):e21800
pubmed: 21789182
Cancer Res. 2002 Jul 1;62(13):3603-8
pubmed: 12097260
Am J Hum Genet. 2016 May 5;98(5):993-1000
pubmed: 27132592
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
EMBO Rep. 2018 Oct;19(10):
pubmed: 30126926
Nat Rev Mol Cell Biol. 2020 May;21(5):268-283
pubmed: 32144406
J Pathol. 2010 Jan;220(2):126-39
pubmed: 19882673
Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2967-2976
pubmed: 30728292
Prostate. 2006 Aug 1;66(11):1203-12
pubmed: 16652388
Nucleic Acids Res. 2020 Jan 8;48(D1):D127-D131
pubmed: 31504780
Cancer Metastasis Rev. 2010 Mar;29(1):123-42
pubmed: 20143131
Am J Hum Genet. 2002 May;70(5):1299-304
pubmed: 11941539
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8105-10
pubmed: 23620512
Epigenetics. 2016 Dec;11(12):871-880
pubmed: 27689475
PLoS One. 2011 Apr 29;6(4):e19152
pubmed: 21559454
Prostate. 2015 Mar 1;75(4):370-80
pubmed: 25421946
Nat Rev Cancer. 2004 Jul;4(7):519-27
pubmed: 15229477
Annu Rev Genet. 2011;45:299-329
pubmed: 21910628
Biol Reprod. 2006 Sep;75(3):352-9
pubmed: 16641145
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):719-24
pubmed: 15647368
Cancer Res. 1999 Jan 15;59(2):279-84
pubmed: 9927031
Prostate. 2011 May;71(6):649-58
pubmed: 20949546
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
F1000Res. 2020 Apr 28;9:304
pubmed: 32489650
Transl Cancer Res. 2020 Feb;9(2):856-868
pubmed: 35117431
Nat Rev Urol. 2012 Feb 21;9(4):196-206
pubmed: 22349653
EMBO Mol Med. 2018 Feb;10(2):219-238
pubmed: 29348142
J Clin Invest. 2008 Sep;118(9):3051-64
pubmed: 18725989
Oncogene. 2016 Feb 25;35(8):1066-72
pubmed: 25982277
Sci Signal. 2014 May 20;7(326):ra47
pubmed: 24847116
Sci Adv. 2017 Aug 16;3(8):e1700677
pubmed: 28835921
Nature. 2019 Sep;573(7774):439-444
pubmed: 31485072
Prostate Cancer. 2019 Jun 19;2019:5974928
pubmed: 31321101
Prostate Cancer Prostatic Dis. 2010 Sep;13(3):270-7
pubmed: 20231859
Trends Genet. 2007 Dec;23(12):614-22
pubmed: 17977614
Adv Exp Med Biol. 2019;1210:351-378
pubmed: 31900917
Prostate Cancer Prostatic Dis. 1999 Mar;2(2):70-75
pubmed: 12496841
Cell Rep. 2016 Aug 16;16(7):1874-90
pubmed: 27498866
J Biol Chem. 1983 Oct 10;258(19):11442-5
pubmed: 6311812
Mol Cell Endocrinol. 2021 May 15;528:111230
pubmed: 33675864
Epigenetics. 2011 Sep 1;6(9):1120-30
pubmed: 21847011
Cancer Res. 2001 Jul 1;61(13):4982-4
pubmed: 11431329
Genome Biol. 2007;8(9):R183
pubmed: 17784955
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
Andrologia. 2019 Feb;51(1):e13169
pubmed: 30311263
Nat Commun. 2019 Mar 1;10(1):1001
pubmed: 30824709
Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):5931-5937
pubmed: 32127478
Front Oncol. 2020 Jun 01;10:809
pubmed: 32547947
J Hum Genet. 2003;48(12):634-638
pubmed: 14625808
Clin Cancer Res. 2012 Oct 15;18(20):5546-53
pubmed: 23071356
Am J Hum Genet. 2001 Apr;68(4):901-11
pubmed: 11254448
Toxicol Pathol. 2003 Jan-Feb;31(1):31-8
pubmed: 12597447
Am J Hum Genet. 2001 Apr;68(4):912-7
pubmed: 11254449
Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3367-71
pubmed: 1565627
Cell Cycle. 2011 Sep 1;10(17):2904-16
pubmed: 21857155
Cancer. 2004 Nov 15;101(10 Suppl):2371-490
pubmed: 15495199
Prostate. 2010 Nov 1;70(15):1716-27
pubmed: 20564318
Genome Biol. 2019 Jan 22;20(1):18
pubmed: 30670076
J Natl Cancer Inst. 2003 Jun 4;95(11):818-24
pubmed: 12783937