AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in castrate-resistant prostate cancer.
AR-V7
cancer biology
human
intranuclear mobility
nuclear import
prostate cancer
transcriptional activity
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
18 07 2022
18 07 2022
Historique:
received:
27
08
2021
accepted:
17
07
2022
pubmed:
19
7
2022
medline:
26
8
2022
entrez:
18
7
2022
Statut:
epublish
Résumé
Expression of the AR splice variant, androgen receptor variant 7 (AR-V7), in prostate cancer is correlated with poor patient survival and resistance to AR targeted therapies and taxanes. Currently, there is no specific inhibitor of AR-V7, while the molecular mechanisms regulating its biological function are not well elucidated. Here, we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567. First, AR-V7 exhibits fast nuclear import kinetics via a pathway distinct from the nuclear localization signal dependent importin-α/β pathway used by AR-fl and AR-v567. We also show that the dimerization box domain, known to mediate AR dimerization and transactivation, is required for AR-V7 nuclear import but not for AR-fl. Once in the nucleus, AR-V7 is transcriptionally active, yet exhibits unusually high intranuclear mobility and transient chromatin interactions, unlike the stable chromatin association of liganded AR-fl. The high intranuclear mobility of AR-V7 together with its high transcriptional output, suggest a Hit-and-Run mode of transcription. Our findings reveal unique mechanisms regulating AR-V7 activity, offering the opportunity to develop selective therapeutic interventions.
Identifiants
pubmed: 35848798
doi: 10.7554/eLife.73396
pii: 73396
pmc: PMC9398446
doi:
pii:
Substances chimiques
AR protein, human
0
Chromatin
0
Protein Isoforms
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA179100
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA062948
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA216800
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA220988
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228512
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA203702
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA137020
Pays : United States
Informations de copyright
© 2022, Kim, Au, Jamalruddin et al.
Déclaration de conflit d'intérêts
SK, CA, MJ, NA, EM, LP, AB, DW, PV, DR, DN, PG No competing interests declared
Références
Cell. 2015 May 21;161(5):1215-1228
pubmed: 26000489
Cell. 2019 Aug 8;178(4):949-963.e18
pubmed: 31353221
Cancer Res. 2010 Oct 15;70(20):7992-8002
pubmed: 20807808
Cancer Cell. 2019 Mar 18;35(3):401-413.e6
pubmed: 30773341
Cancer Res. 2009 Jan 1;69(1):16-22
pubmed: 19117982
J Cell Sci. 2012 Apr 15;125(Pt 8):1970-9
pubmed: 22328501
Bioessays. 2019 Aug;41(8):e1900041
pubmed: 31245868
Cancer Res. 2014 Apr 15;74(8):2270-2282
pubmed: 24556717
Cancer Res. 2011 Sep 15;71(18):6019-29
pubmed: 21799031
Endocrinology. 2008 Aug;149(8):3960-9
pubmed: 18420738
Oncogene. 2021 Feb;40(6):1106-1117
pubmed: 33323969
PLoS One. 2017 Jun 1;12(6):e0177861
pubmed: 28570625
Oncotarget. 2014 Mar 30;5(6):1646-56
pubmed: 24722067
Traffic. 2005 Mar;6(3):187-98
pubmed: 15702987
Clin Cancer Res. 2019 Mar 15;25(6):1880-1888
pubmed: 30301829
Mol Cell. 2013 Feb 21;49(4):730-42
pubmed: 23333309
Mol Cell Biol. 2000 Sep;20(17):6466-75
pubmed: 10938123
Nat Methods. 2015 Mar;12(3):215-8, 4 p following 218
pubmed: 25581799
Nat Rev Cancer. 2015 Dec;15(12):701-11
pubmed: 26563462
J Biol Chem. 1994 May 6;269(18):13115-23
pubmed: 8175737
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6810-6815
pubmed: 29844167
Cancer Res. 2009 Mar 15;69(6):2305-13
pubmed: 19244107
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7496-501
pubmed: 12032311
J Cell Biol. 1987 Feb;104(2):189-200
pubmed: 3805121
Prostate Cancer Prostatic Dis. 2016 Sep;19(3):231-41
pubmed: 27184811
PLoS One. 2011 Apr 28;6(4):e19059
pubmed: 21552559
J Clin Oncol. 2017 Oct 1;35(28):3181-3188
pubmed: 28632486
N Engl J Med. 2014 Sep 11;371(11):1028-38
pubmed: 25184630
Expert Opin Ther Targets. 2018 Mar;22(3):201-216
pubmed: 29417861
Science. 2000 Feb 18;287(5456):1262-5
pubmed: 10678832
Bioessays. 2015 Jul;37(7):748-54
pubmed: 26010075
J Struct Biol. 2004 Jul;147(1):50-61
pubmed: 15109605
Mol Cell Biol. 2007 Mar;27(5):1823-43
pubmed: 17189428
Bioorg Med Chem. 2020 Oct 15;28(20):115712
pubmed: 33069070
Mol Cell Biol. 2001 Jul;21(13):4404-12
pubmed: 11390668
Mol Biol Cell. 2010 Oct 1;21(19):3433-42
pubmed: 20685962
Biochem J. 1993 Aug 1;293 ( Pt 3):761-8
pubmed: 8352744
J Clin Invest. 2010 Aug;120(8):2715-30
pubmed: 20644256
Mol Endocrinol. 2008 Nov;22(11):2373-82
pubmed: 18617596
Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16759-65
pubmed: 20823238
Pathol Res Pract. 2021 Jun;222:153440
pubmed: 33857854
J Biol Chem. 2012 Jun 1;287(23):19736-49
pubmed: 22532567
Cancer Res. 2013 Jan 15;73(2):483-9
pubmed: 23117885
Curr Treat Options Oncol. 2015 Dec;16(12):57
pubmed: 26537882
Nat Rev Cancer. 2001 Oct;1(1):34-45
pubmed: 11900250
Exp Cell Res. 1987 Dec;173(2):586-95
pubmed: 2446896
Cancer Res. 2015 Sep 1;75(17):3663-71
pubmed: 26060018
J Cell Sci. 2005 Sep 15;118(Pt 18):4187-98
pubmed: 16141232