Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 11 2021
04 11 2021
Historique:
received:
16
08
2021
accepted:
04
10
2021
entrez:
5
11
2021
pubmed:
6
11
2021
medline:
24
12
2021
Statut:
epublish
Résumé
Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.
Identifiants
pubmed: 34737261
doi: 10.1038/s41467-021-26612-1
pii: 10.1038/s41467-021-26612-1
pmc: PMC8568894
doi:
Substances chimiques
AR protein, human
0
KLF5 protein, human
0
Kruppel-Like Transcription Factors
0
Receptors, Androgen
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
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
6377Subventions
Organisme : NCI NIH HHS
ID : R01 CA229618
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204856
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA174777
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA241486
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA212097
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA230617
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Biochem J. 2009 Jan 1;417(1):313-22
pubmed: 18774944
Nat Commun. 2018 Jun 19;9(1):2404
pubmed: 29921838
Science. 2017 Jan 6;355(6320):84-88
pubmed: 28059768
Nucleic Acids Res. 2015 Jul 13;43(12):5880-97
pubmed: 25908785
Int J Cancer. 2006 Mar 15;118(6):1346-55
pubmed: 16184550
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Genes Cancer. 2012 Feb;3(2):102-16
pubmed: 23050043
Cell. 2015 May 21;161(5):1215-1228
pubmed: 26000489
Cancer Cell. 2017 Dec 11;32(6):792-806.e7
pubmed: 29153843
Cell. 2014 Sep 25;159(1):176-187
pubmed: 25201530
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Neoplasia. 2014 Nov 20;16(11):883-99
pubmed: 25425963
Cancer Cell. 2011 Oct 18;20(4):457-71
pubmed: 22014572
Nat Med. 2016 Apr;22(4):369-78
pubmed: 26928463
Nat Commun. 2020 Feb 21;11(1):997
pubmed: 32081850
Cancer Res. 2011 Mar 15;71(6):2108-17
pubmed: 21248069
Sci Transl Med. 2019 Jul 31;11(503):
pubmed: 31366581
Nucleic Acids Res. 2019 Jan 8;47(D1):D745-D751
pubmed: 30407521
PLoS One. 2016 Nov 30;11(11):e0166731
pubmed: 27902734
Nat Cell Biol. 2008 Mar;10(3):353-60
pubmed: 18264089
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17492-7
pubmed: 24101480
Cancer Res. 1994 May 15;54(10):2577-81
pubmed: 8168083
Nucleic Acids Res. 2012 May;40(10):4288-97
pubmed: 22287627
Mol Endocrinol. 2009 Sep;23(9):1385-96
pubmed: 19460858
Clin Cancer Res. 2019 Dec 1;25(23):6916-6924
pubmed: 31363002
Cancer Discov. 2018 Jan;8(1):108-125
pubmed: 28963353
Cancer Cell. 2016 Oct 10;30(4):563-577
pubmed: 27728805
Cancer Cell. 2004 Nov;6(5):517-27
pubmed: 15542435
Nat Rev Cancer. 2015 Dec;15(12):701-11
pubmed: 26563462
Nucleic Acids Res. 2013 May 1;41(10):e108
pubmed: 23558742
Differentiation. 2008 Jul;76(6):682-98
pubmed: 18462434
Cancers (Basel). 2020 Mar 21;12(3):
pubmed: 32245249
Gut. 2015 May;64(5):707-19
pubmed: 25053715
Clin Cancer Res. 2006 Apr 15;12(8):2442-8
pubmed: 16638850
Cell Rep. 2015 Aug 11;12(6):922-36
pubmed: 26235627
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436
pubmed: 31061129
Prostate. 2003 May 1;55(2):81-8
pubmed: 12661032
Nat Commun. 2021 Mar 17;12(1):1714
pubmed: 33731701
Cancer Res. 2012 Sep 1;72(17):4504-14
pubmed: 22745369
Nat Commun. 2019 Jan 17;10(1):278
pubmed: 30655535
Clin Cancer Res. 2016 Jul 15;22(14):3672-82
pubmed: 26936914
Nat Genet. 2016 Feb;48(2):176-82
pubmed: 26656844
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
J Clin Oncol. 2011 Sep 20;29(27):3651-8
pubmed: 21859989
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Gastroenterology. 2008 Jan;134(1):120-30
pubmed: 18054006
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Urol Oncol. 2013 Jan;31(1):82-6
pubmed: 21396844
Nat Med. 2016 Mar;22(3):298-305
pubmed: 26855148
Prostate. 2018 Sep;78(13):981-991
pubmed: 29790189
Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):644-9
pubmed: 26721396
Nucleic Acids Res. 2019 Jan 8;47(D1):D729-D735
pubmed: 30462313
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
Cancer Discov. 2017 Jan;7(1):54-71
pubmed: 27784708
Cancer Res. 2006 Apr 1;66(7):3903-11
pubmed: 16585219
Differentiation. 2018 Sep - Oct;103:24-45
pubmed: 30224091
Cell Death Dis. 2020 Jun 16;11(6):466
pubmed: 32546700
Cancer Res. 2012 Jul 15;72(14):3457-62
pubmed: 22710436
Cell Rep. 2018 Dec 18;25(12):3530-3542.e5
pubmed: 30566875
Nat Methods. 2015 Apr;12(4):357-60
pubmed: 25751142
Cancer Res. 2017 Jul 1;77(13):3417-3430
pubmed: 28473532
Oncotarget. 2015 Apr 20;6(11):9086-98
pubmed: 25871401
Cancer Res. 2013 Jan 15;73(2):483-9
pubmed: 23117885
Genome Biol. 2014 Mar 03;15(3):R47
pubmed: 24580837
Endocr Relat Cancer. 2015 Dec;22(6):T187-97
pubmed: 26307022
Endocr Relat Cancer. 2020 Feb;27(2):R35-R50
pubmed: 31804971
Life Sci Alliance. 2018 Dec 28;2(1):e201800115
pubmed: 30620009