An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis.
Adenosine Triphosphate
/ metabolism
Adult
Animals
Breast Neoplasms
/ genetics
CSK Tyrosine-Protein Kinase
Carcinogenesis
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein
/ genetics
Epigenesis, Genetic
Female
Humans
Mammary Glands, Human
/ metabolism
Mechanistic Target of Rapamycin Complex 1
/ genetics
Mice
Mice, Inbred NOD
Mice, Transgenic
Middle Aged
Mitochondria
/ genetics
Polycomb Repressive Complex 2
/ genetics
Protein Biosynthesis
Receptor, ErbB-2
/ genetics
src-Family Kinases
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
23
08
2018
accepted:
24
05
2019
entrez:
3
7
2019
pubmed:
3
7
2019
medline:
26
9
2019
Statut:
epublish
Résumé
Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
Identifiants
pubmed: 31263101
doi: 10.1038/s41467-019-10681-4
pii: 10.1038/s41467-019-10681-4
pmc: PMC6603039
doi:
Substances chimiques
Adenosine Triphosphate
8L70Q75FXE
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Polycomb Repressive Complex 2
EC 2.1.1.43
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
CSK Tyrosine-Protein Kinase
EC 2.7.10.2
src-Family Kinases
EC 2.7.10.2
CSK protein, human
EC 2.7.10.23
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
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
2901Subventions
Organisme : NCI NIH HHS
ID : K00 CA212221
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA212221
Pays : United States
Organisme : United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)
ID : W81XWH-11-1-0046
Pays : International
Organisme : CIHR
Pays : Canada
Organisme : NIDDK NIH HHS
ID : K25 DK115904
Pays : United States
Organisme : Terry Fox Research Institute (Institut de Recherche Terry Fox)
ID : 1048
Pays : International
Références
Nat Commun. 2018 Jun 29;9(1):2547
pubmed: 29959321
Cell Cycle. 2016 Sep;15(17):2256-62
pubmed: 27419533
Cancer Metab. 2013 Aug 14;1(1):18
pubmed: 24280377
Genome Res. 2016 May;26(5):636-48
pubmed: 26984228
Biochem J. 2012 Oct 15;447(2):281-9
pubmed: 22823520
Int J Cancer. 2016 Feb 1;138(3):747-57
pubmed: 26284485
EMBO J. 2008 Mar 19;27(6):910-20
pubmed: 18273058
Mol Oncol. 2012 Oct;6(5):494-506
pubmed: 22766277
Genes Dev. 2015 Dec 15;29(24):2547-62
pubmed: 26637281
Science. 1987 Jan 9;235(4785):177-82
pubmed: 3798106
Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8977-82
pubmed: 22611195
Clin Cancer Res. 2016 Jul 1;22(13):3249-59
pubmed: 26842237
Int J Cancer. 2007 Mar 1;120(5):995-1004
pubmed: 17131343
Trends Cell Biol. 2016 Dec;26(12):918-933
pubmed: 27426745
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11
pubmed: 14500907
Biochem J. 2010 Jan 27;426(1):109-18
pubmed: 19958286
J Biol Chem. 2003 May 2;278(18):15789-93
pubmed: 12600984
Mol Cell. 2008 Apr 25;30(2):214-26
pubmed: 18439900
Nature. 2012 Dec 6;492(7427):108-12
pubmed: 23051747
Nat Commun. 2018 Oct 19;9(1):4351
pubmed: 30341294
Bioinformatics. 2011 May 15;27(10):1440-1
pubmed: 21422072
Mol Cell. 2008 Nov 21;32(4):491-502
pubmed: 19026780
Nature. 2012 Feb 22;485(7396):55-61
pubmed: 22367541
J Vis Exp. 2014 May 17;(87):
pubmed: 24893926
Oncogene. 2011 Sep 29;30(39):4118-28
pubmed: 21499305
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Mol Cell Biol. 2009 Nov;29(21):5858-71
pubmed: 19704002
Nature. 2011 Jan 20;469(7330):343-9
pubmed: 21248841
Cell Metab. 2018 Dec 4;28(6):833-847.e8
pubmed: 30174304
Elife. 2016 Jan 27;5:
pubmed: 26814573
Curr Opin Cell Biol. 2015 Apr;33:1-7
pubmed: 25259783
Mol Carcinog. 2015 Oct;54(10):1172-80
pubmed: 25043748
J Biol Chem. 2012 Nov 9;287(46):38625-36
pubmed: 23027865
Mol Cell Biol. 2001 Jun;21(12):3995-4004
pubmed: 11359907
Science. 1994 Mar 18;263(5153):1609-12
pubmed: 8128248
Cell Rep. 2013 Feb 21;3(2):411-26
pubmed: 23375371
Mol Cell. 2016 Jun 2;62(5):695-711
pubmed: 27259202
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7
pubmed: 23620515
Br J Cancer. 2006 Nov 20;95(10):1410-4
pubmed: 17060931
Nat Rev Cancer. 2016 Dec;16(12):803-810
pubmed: 27658528
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1415-20
pubmed: 9990038
Cancer Metab. 2013 Dec 05;1(1):22
pubmed: 24304688
Nat Cell Biol. 2015 Oct;17(10):1304-16
pubmed: 26322680
J Immunol. 2005 Jan 1;174(1):180-94
pubmed: 15611240
Cell Metab. 2010 May 5;11(5):390-401
pubmed: 20444419
Mol Cell. 1999 Dec;4(6):915-24
pubmed: 10635317
Science. 2009 May 22;324(5930):1076-80
pubmed: 19461003
Histopathology. 2016 Jul;69(1):25-34
pubmed: 26588661
Cell Metab. 2013 Nov 5;18(5):698-711
pubmed: 24206664
J Cell Sci. 2008 Mar 15;121(Pt 6):804-13
pubmed: 18285444
Cancer Metab. 2014 Aug 28;2:12
pubmed: 25184038
Cell. 2003 Nov 26;115(5):577-90
pubmed: 14651849
Cancer Res. 2007 Nov 15;67(22):10804-12
pubmed: 18006825
Nature. 2007 Nov 29;450(7170):736-40
pubmed: 18046414
Nat Cell Biol. 2015 Apr;17(4):351-9
pubmed: 25774832
J Med Chem. 2016 May 26;59(10):4697-710
pubmed: 27115835
Cancer Cell. 2016 Apr 11;29(4):548-562
pubmed: 27052953
Nucleic Acids Res. 2015 Oct 15;43(18):8774-89
pubmed: 26250110
Biochem J. 2000 Jun 15;348 Pt 3:607-14
pubmed: 10839993
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2808-13
pubmed: 21628573
Br J Cancer. 2009 Jan 13;100(1):123-33
pubmed: 19066611
Nature. 1994 Oct 27;371(6500):762-7
pubmed: 7935836
Mol Cell. 2016 Dec 15;64(6):1074-1087
pubmed: 27889452
Nat Commun. 2017 Jan 05;8:13732
pubmed: 28054552
J Biol Chem. 2002 May 3;277(18):15813-8
pubmed: 11867640
Biochim Biophys Acta. 2012 May;1817(5):718-25
pubmed: 22321370
Leukemia. 2017 Nov;31(11):2326-2335
pubmed: 28280275
Nat Methods. 2009 Apr;6(4):275-7
pubmed: 19305406
PLoS One. 2016 Nov 22;11(11):e0166438
pubmed: 27875550
Stem Cells. 2013 Sep;31(9):1910-20
pubmed: 23712803
Mol Cell Biol. 2007 May;27(10):3769-79
pubmed: 17339329