Alternative promoters control UGT2B17-dependent androgen catabolism in prostate cancer and its influence on progression.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
05
08
2019
accepted:
23
01
2020
revised:
18
12
2019
pubmed:
13
2
2020
medline:
16
1
2021
entrez:
13
2
2020
Statut:
ppublish
Résumé
Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution. We conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data. UGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa. The androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.
Sections du résumé
BACKGROUND
Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution.
METHODS
We conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data.
RESULTS
UGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa.
CONCLUSIONS
The androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.
Identifiants
pubmed: 32047296
doi: 10.1038/s41416-020-0749-2
pii: 10.1038/s41416-020-0749-2
pmc: PMC7109100
doi:
Substances chimiques
Androgens
0
Minor Histocompatibility Antigens
0
Glucuronosyltransferase
EC 2.4.1.17
UGT2B17 protein, human
EC 2.4.1.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1068-1076Subventions
Organisme : CIHR
Pays : Canada
Références
BMC Cancer. 2007 Apr 12;7:64
pubmed: 17430594
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Cancer Res. 2008 Jun 1;68(11):4447-54
pubmed: 18519708
Eur Urol. 2014 Apr;65(4):683-9
pubmed: 23340241
Expert Opin Pharmacother. 2013 Jan;14(1):91-6
pubmed: 23199349
Drug Metab Dispos. 2008 Nov;36(11):2307-15
pubmed: 18719240
Endocrinology. 1997 Jul;138(7):2998-3005
pubmed: 9202245
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11890-5
pubmed: 12185249
N Engl J Med. 2012 Sep 27;367(13):1187-97
pubmed: 22894553
Trends Endocrinol Metab. 2003 Dec;14(10):473-9
pubmed: 14643063
Eur Urol. 2011 Dec;60(6):1226-34
pubmed: 21715084
Eur Urol. 2018 Nov;74(5):585-594
pubmed: 30077399
Prostate. 2008 Jun 1;68(8):839-48
pubmed: 18302198
Clin Cancer Res. 2019 Jan 1;25(1):426-439
pubmed: 30181386
J Clin Endocrinol Metab. 2012 Mar;97(3):E428-32
pubmed: 22170718
Haematologica. 2016 Feb;101(2):e63-5
pubmed: 26589911
Protein Pept Lett. 2012 Jan;19(1):62-9
pubmed: 21919858
Biochemistry. 2001 Apr 3;40(13):3869-81
pubmed: 11300766
Eur Urol Focus. 2016 Dec;2(5):499-505
pubmed: 28723515
J Clin Invest. 2019 Jan 2;129(1):192-208
pubmed: 30334814
Pharmacogenetics. 1997 Aug;7(4):317-25
pubmed: 9295060
Cancer Cell. 2010 Jul 13;18(1):11-22
pubmed: 20579941
Drug Metab Rev. 2010 Feb;42(1):24-44
pubmed: 19857043
Mol Pharmacol. 2010 Oct;78(4):714-22
pubmed: 20628005
Blood. 2013 Feb 14;121(7):1175-83
pubmed: 23169782
CA Cancer J Clin. 2019 Sep;69(5):363-385
pubmed: 31184787
N Engl J Med. 2014 Jul 31;371(5):424-33
pubmed: 24881730
N Engl J Med. 2011 May 26;364(21):1995-2005
pubmed: 21612468
Eur Urol. 2016 Apr;69(4):601-609
pubmed: 26215610
J Proteome Res. 2014 Feb 7;13(2):1088-100
pubmed: 24359151
Nature. 2012 Jul 12;487(7406):239-43
pubmed: 22722839
Clin Pharmacol Ther. 2014 Sep;96(3):324-39
pubmed: 24922307
Drug Metab Dispos. 2019 May;47(5):444-452
pubmed: 30819787
ISRN Oncol. 2013 Sep 09;2013:465916
pubmed: 24106614
J Clin Oncol. 2017 Sep 20;35(27):3097-3104
pubmed: 28796587
Cancer Res. 2016 Nov 15;76(22):6701-6711
pubmed: 27659047
Clin Cancer Res. 2014 Jun 1;20(11):2971-83
pubmed: 24682418
J Biol Chem. 1996 Sep 13;271(37):22855-62
pubmed: 8798464
Horm Cancer. 2016 Apr;7(2):104-13
pubmed: 26797685
Methods Enzymol. 2005;400:116-47
pubmed: 16399347
Clin Cancer Res. 2018 Nov 1;24(21):5305-5312
pubmed: 30021911
Oncogene. 2014 Jun 12;33(24):3140-50
pubmed: 23851510
BMC Cancer. 2017 Jul 3;17(1):463
pubmed: 28673330
Endocrinology. 1996 Jul;137(7):2872-9
pubmed: 8770908
Eur Urol. 2016 Apr;69(4):610-612
pubmed: 26318705
Pharmacogenomics J. 2016 Feb;16(1):60-70
pubmed: 25869014
DNA Cell Biol. 1997 Oct;16(10):1143-54
pubmed: 9364925