Crosstalk between androgen and pro-inflammatory signaling remodels androgen receptor and NF-κB cistrome to reprogram the prostate cancer cell transcriptome.
Inflammatory processes and androgen signaling are critical for the growth of prostate cancer (PC), the most common cancer among males in Western countries. To understand the importance of potential interplay between pro-inflammatory and androgen signaling for gene regulation, we have interrogated the crosstalk between androgen receptor (AR) and NF-κB, a key transcriptional mediator of inflammatory responses, by utilizing genome-wide chromatin immunoprecipitation sequencing and global run-on sequencing in PC cells. Co-stimulation of LNCaP cells with androgen and pro-inflammatory cytokine TNFα invoked a transcriptome which was very distinct from that induced by either stimulation alone. The altered transcriptome that included gene programs linked to cell migration and invasiveness was orchestrated by significant remodeling of NF-κB and AR cistrome and enhancer landscape. Although androgen multiplied the NF-κB cistrome and TNFα restrained the AR cistrome, there was no general reciprocal tethering of the AR to the NF-κB on chromatin. Instead, redistribution of FOXA1, PIAS1 and PIAS2 contributed to the exposure of latent NF-κB chromatin-binding sites and masking of AR chromatin-binding sites. Taken together, concomitant androgen and pro-inflammatory signaling significantly remodels especially the NF-κB cistrome, reprogramming the PC cell transcriptome in fashion that may contribute to the progression of PC.
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland.
Marjo
M
Malinen
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland.
Einari A
EA
Niskanen
A.I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland.
Minna U
MU
Kaikkonen
Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland jorma.palvimo@uef.fi.
Jorma J
JJ
Palvimo
D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D059467:Transcriptome
D000728:Androgens; D002843:Chromatin; D016207:Cytokines; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D018836:Inflammation Mediators; D016328:NF-kappa B; C501001:PIAS2 protein, human; D050828:Protein Inhibitors of Activated STAT; D011944:Receptors, Androgen
Int J Cancer. 2007 Sep 1;121(5):999-1008
17487836
Nucleic Acids Res. 2014 Apr;42(7):4230-40
24459135
Science. 2009 Apr 10;324(5924):218-23
19213877
Genome Res. 2015 Sep;25(9):1281-94
26113076
Nucleic Acids Res. 2014 Nov 10;42(20):12570-84
25352550
BJU Int. 2009 Nov;104(9):1191-7
19624596
Mol Cell Endocrinol. 2015 Oct 15;414:91-8
26219822
J Biol Chem. 1996 Sep 27;271(39):24151-6
8798655
Bioinformatics. 2010 Jan 1;26(1):139-40
19910308
BJU Int. 2014 Aug;114(2):168-76
24215139
Cell. 2007 Jun 1;129(5):903-14
17540171
Nucleic Acids Res. 2014 Feb;42(3):1575-92
24194604
Am J Pathol. 2012 May;180(5):2097-107
22449952
Clin Cancer Res. 2009 Aug 1;15(15):4792-8
19638458
Mol Cell. 2015 Apr 2;58(1):21-34
25752574
Cancer Res. 2013 Mar 1;73(5):1570-80
23269278
Pharmacol Ther. 2013 Dec;140(3):223-38
23859952
Methods Mol Biol. 2011;776:183-97
21796528
Nat Rev Cancer. 2012 May 04;12(6):381-5
22555282
Genes Dev. 2006 Jun 1;20(11):1405-28
16751179
Cell Mol Life Sci. 2009 Sep;66(18):3029-41
19526197
Oncogene. 1999 Nov 22;18(49):6853-66
10602461
Oncogene. 2016 May 5;35(18):2322-32
26257066
Cell. 2016 Apr 21;165(3):593-605
27062924
J Biol Chem. 1999 Feb 5;274(6):3700-4
9920921
Mol Cell. 2010 May 28;38(4):576-89
20513432
Int J Cancer. 2007 Feb 15;120(4):719-33
17163421
Front Oncol. 2015 Jul 08;5:128
26217583
EMBO J. 2011 Sep 13;30(19):3962-76
21915096
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2122-7
9482849
Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141
20066113
Genome Res. 2013 Aug;23(8):1210-23
23636943
PLoS One. 2013;8(4):e60983
23577181
Nature. 2010 Mar 11;464(7286):302-5
20220849
Genome Res. 2011 Sep;21(9):1404-16
21750107
J Urol. 2000 Sep;164(3 Pt 1):800-5
10953159
Nat Methods. 2012 Jun 28;9(7):676-82
22743772
Cold Spring Harb Perspect Biol. 2009 Oct;1(4):a000034
20066092
Cell. 2013 Sep 12;154(6):1190-3
24034243
Genome Biol. 2015 Jul 28;16:153
26259101
Mol Endocrinol. 2003 Aug;17(8):1484-507
12750453
PLoS One. 2009;4(1):e4173
19137064
Nature. 2011 May 15;474(7351):390-4
21572438
J Biol Chem. 1997 Jun 20;272(25):15973-9
9188499
Mol Endocrinol. 2014 Jul;28(7):989-98
24825399
Mol Cell Biol. 2005 Feb;25(3):1113-23
15657437
Mol Endocrinol. 2014 Oct;28(10):1719-28
25127374
Mol Endocrinol. 2008 Feb;22(2):273-86
17975021
Nucleic Acids Res. 2015 Jan;43(2):848-61
25552417
Nucleic Acids Res. 2014 Jul;42(13):8310-9
24981513
Oncotarget. 2015 Feb 10;6(4):2263-76
25537508
Cytokine. 2013 Nov;64(2):555-63
24063999