Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
15
11
2018
accepted:
09
12
2019
entrez:
11
1
2020
pubmed:
11
1
2020
medline:
14
4
2020
Statut:
epublish
Résumé
Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.
Identifiants
pubmed: 31923184
doi: 10.1371/journal.pgen.1008558
pii: PGENETICS-D-18-02188
pmc: PMC6953790
doi:
Substances chimiques
BECN1 protein, human
0
Beclin-1
0
MAP1LC3B protein, human
0
Microtubule-Associated Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008558Subventions
Organisme : NCI NIH HHS
ID : R00 CA207729
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA207729
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM132055
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA102310
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG033082
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM113278
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA107263
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA138313
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA177519
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247562
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Cancer Discov. 2014 Aug;4(8):914-27
pubmed: 24875857
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Nat Commun. 2016 Nov 21;7:13508
pubmed: 27869116
Curr Mol Pharmacol. 2011 Nov;4(3):167-75
pubmed: 21222647
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Comput Methods Programs Biomed. 2016 Sep;133:143-154
pubmed: 27393806
Biostatistics. 2004 Oct;5(4):557-72
pubmed: 15475419
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82
pubmed: 14657337
Nat Commun. 2017 Feb 15;8:14423
pubmed: 28198375
Cancer Res. 1991 Jun 1;51(11):2979-84
pubmed: 2032235
Cancer Discov. 2013 Nov;3(11):1272-85
pubmed: 23965987
BMC Med Genomics. 2015 Feb 18;8:5
pubmed: 25889064
Mol Cancer Res. 2014 Apr;12(4):485-90
pubmed: 24478461
Autophagy. 2014;10(11):2036-52
pubmed: 25483966
Oncotarget. 2015 Oct 13;6(31):31104-18
pubmed: 26418751
J Clin Invest. 2003 Dec;112(12):1809-20
pubmed: 14638851
Rejuvenation Res. 2005 Spring;8(1):3-5
pubmed: 15798367
Cell. 2008 Jan 11;132(1):27-42
pubmed: 18191218
Cell Rep. 2016 May 24;15(8):1660-72
pubmed: 27184837
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
PLoS Med. 2015 Feb 24;12(2):e1001789
pubmed: 25710373
Cancer Biol Ther. 2007 Nov;6(11):1717-25
pubmed: 17986851
Genes Dev. 2016 Aug 1;30(15):1704-17
pubmed: 27516533
Genes Dev. 2007 Jun 1;21(11):1367-81
pubmed: 17510285
EMBO Rep. 2013 Apr;14(4):364-72
pubmed: 23478334
Cell. 2013 Nov 7;155(4):948-62
pubmed: 24183448
Nature. 2010 Jul 1;466(7302):68-76
pubmed: 20562859
Autophagy. 2016;12(2):357-68
pubmed: 26565512
Nat Med. 2016 Jan;22(1):105-13
pubmed: 26618723
Genes Dev. 2011 Mar 1;25(5):460-70
pubmed: 21317241
Breast Cancer Res Treat. 2010 Oct;123(3):725-31
pubmed: 20020197
J Biosci. 2012 Jul;37(3):503-17
pubmed: 22750987
Autophagy. 2016;12(1):1-222
pubmed: 26799652
Genome Res. 2012 Jun;22(6):993-1005
pubmed: 22456607
Cell. 2018 Apr 5;173(2):499-514.e23
pubmed: 29576454
Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):773-8
pubmed: 25568088
Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001107
pubmed: 20182618
EBioMedicine. 2015 Mar;2(3):255-263
pubmed: 25825707
Nature. 2016 Mar 24;531(7595):471-475
pubmed: 26982726
J Ovarian Res. 2015 Aug 04;8:52
pubmed: 26239434
Mol Biotechnol. 2004 Mar;26(3):249-61
pubmed: 15004294
Nature. 1999 Dec 9;402(6762):672-6
pubmed: 10604474
Nat Rev Cancer. 2012 Apr 26;12(6):401-10
pubmed: 22534666
J Cell Sci. 2016 Oct 15;129(20):3685-3693
pubmed: 27672021
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Cancer Discov. 2016 Dec;6(12):1342-1351
pubmed: 27856443
Autophagy. 2016 Oct 2;12(10):1917-1930
pubmed: 27391408
Semin Cancer Biol. 2001 Feb;11(1):15-23
pubmed: 11243895
PLoS One. 2017 Oct 20;12(10):e0186043
pubmed: 29053726
Nat Genet. 2017 Jun;49(6):856-865
pubmed: 28436987
Cell. 2016 Feb 11;164(4):644-55
pubmed: 26871630
Sci Rep. 2016 May 18;6:26191
pubmed: 27189670
Am J Pathol. 2010 Sep;177(3):1053-64
pubmed: 20651229
PLoS One. 2015 Sep 17;10(9):e0137675
pubmed: 26378792
Gynecol Oncol. 2016 Aug;142(2):332-40
pubmed: 27235858
Cancer Discov. 2012 Aug;2(8):679-84
pubmed: 22843421
FASEB J. 2016 Dec;30(12):3961-3978
pubmed: 27601442
PLoS Genet. 2018 Sep 13;14(9):e1007669
pubmed: 30212491
Oncogenesis. 2017 Jan 30;6(1):e295
pubmed: 28134933