A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 07 2020
17 07 2020
Historique:
received:
28
10
2019
accepted:
24
06
2020
entrez:
19
7
2020
pubmed:
19
7
2020
medline:
20
9
2020
Statut:
epublish
Résumé
Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry. One such African ancestry specific rare variant, rs72725854 (A>G/T) (~6% allele frequency) has been associated with a ~2-fold increase in prostate cancer risk. However, the functional relevance of this variant is unknown. Here we show that the variant rs72725854 is present in a prostate cancer-specific enhancer at 8q24 locus. Chromatin-conformation capture and dCas9 mediated enhancer blocking establish a direct regulatory link between this enhancer and lncRNAs PCAT1, PRNCR1 and PVT1. The risk allele ('T') is associated with higher expression of PCAT1, PVT1 and c-myc in prostate tumors. Further, enhancer with the risk allele gains response to androgen stimulation by recruiting the transcription factor SPDEF whereas, non-risk alleles remain non-responsive. Elevated expression of these lncRNAs and c-myc in risk allele carriers may explain their greater susceptibility to prostate cancer.
Identifiants
pubmed: 32680982
doi: 10.1038/s41467-020-17325-y
pii: 10.1038/s41467-020-17325-y
pmc: PMC7368061
doi:
Substances chimiques
RNA, Long Noncoding
0
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
3598Subventions
Organisme : DBT-Wellcome Trust India Alliance
ID : IA/I/14/2/501539
Pays : India
Organisme : NCI NIH HHS
ID : R01 CA227237
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193910
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Références
Freedman, M. L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl Acad. Sci. USA 103, 14068–14073 (2006).
pubmed: 16945910
Haiman, C. A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet 39, 638–44 (2007).
pubmed: 17401364
pmcid: 2638766
Matejcic, M. et al. Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nat. Commun. 9, 4616 (2018).
pubmed: 30397198
pmcid: 6218483
de Bakker, P. I. et al. Transferability of tag SNPs in genetic association studies in multiple populations. Nat. Genet. Nov. 38, 1298–303 (2006).
Han, Y. et al. Prostate cancer susceptibility in men of African ancestry at 8q24. JNCI 108, djv431 (2016).
Haiman, C. A. et al. A common genetic risk factor for colorectal and prostate cancer. Nat. Genet. 39, 954 (2007).
pubmed: 17618282
pmcid: 2391283
Conti, D. V. et al. Two novel susceptibility loci for prostate cancer in men of African ancestry. JNCI. 109, djx084 (2017).
Darst, B. F. et al. A germline variant at 8q24 contributes to familial clustering of prostate cancer in men of African ancestry. Eur. Urol. https://doi.org/10.1016/j.eururo.2020.04.060 (2020).
doi: 10.1016/j.eururo.2020.04.060
pubmed: 32409115
Guo, H. et al. Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat. Genet. 48, 1142–1150 (2016).
pubmed: 27526323
Yuan, Q. et al. LncRNA PCAT1 and its genetic variant rs1902432 are associated with prostate cancer risk. J. Cancer 9, 1414–1420 (2018).
pubmed: 29721051
pmcid: 5929086
Wan, B. et al. Downregulation of lncRNA PVT1 expression inhibits proliferation and migration by regulating p38 expression in prostate cancer. Oncol. Lett. 16, 5160–5166 (2018).
pubmed: 30250582
pmcid: 6144883
Yang, L. et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500, 598–602 (2013).
pubmed: 23945587
pmcid: 4034386
Du, Z. et al. Genetic risk of prostate cancer in Ugandan men. Prostate 78, 370–376 (2018).
pubmed: 29356057
Chen, H. et al. Long non-coding RNA CCAT1 promotes the migration and invasion of prostate cancer PC-3 cells. Eur. Rev. Med Pharm. Sci. 22, 2991–2996 (2018).
Zheng, J. et al. The up-regulation of long non-coding RNA CCAT2 indicates a poor prognosis for prostate cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Biochem. Biophys. Res. Commun. 480, 508–514 (2016).
pubmed: 27558961
Grisanzio, C. & Freedman, M. Chromosome 8q24-associated cancers and MYC. Genes Cancer 1, 555–9 (2010).
pubmed: 21779458
pmcid: 3092220
Gusev, A. et al. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nat. Commun. 7, 10979 (2016).
pubmed: 27052111
pmcid: 4829663
Sun, W. et al. Integrative analysis of super enhancer SNPs for type 2 diabetes. PLoS ONE. 13, e0192105 (2018).
MacKenzie, A., Hing, B. & Davidson, S. Exploring the effects of polymorphisms on cis-regulatory signal transduction response. Trends Mol. Med. 19, 99–107 (2013).
pubmed: 23265842
pmcid: 3569712
Fazlollahi, M. et al. Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets. Biochem. Biophys. Res. Commun. 480, 508–514 (2016).
De Santa, F. et al. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010).
Caravaca, J. M. et al. Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes Dev. 27, 251–60 (2013).
pubmed: 23355396
pmcid: 3576511
Lonergan, P. E. & Tindall, D. J. Androgen receptor signaling in prostate cancer development and progression. J. Carcinog. 10, 20 (2011).
pubmed: 21886458
pmcid: 3162670
Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).
pubmed: 23728302
pmcid: 3718886
Hsieh, C. L. et al. Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc. Natl Acad. Sci. USA 111, 7319–24 (2014).
pubmed: 24778216
Whalen, S., Truty, R. M. & Pollard, K. S. Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat. Genet. 48, 488–96 (2016).
pubmed: 27064255
pmcid: 4910881
Lupianez, D. G., Spielmann, M. & Mundlos, S. Breaking TADs: how alterations of chromatin domains result in disease. Trends Genet. 32, 225–37 (2016).
pubmed: 26862051
Dunham, I. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
Tseng, Y. Y. & Bagchi, A. The PVT1-MYC duet in cancer. Mol. Cell Oncol. 2, e974467 (2015).
Carramusa, L. et al. The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. J. Cell Physiol. 213, 511–518 (2007).
pubmed: 17503467
Tseng, Y. Y. et al. PVT1 dependence in cancer with MYC copy-number increase. Nature 512, 82–86 (2014).
pubmed: 25043044
pmcid: 4767149
Wei, G. et al. Genome‐wide analysis of ETS‐family DNA‐binding in vitro and in vivo. EMBO J. 29, 2147–2160 (2010).
pubmed: 20517297
pmcid: 2905244
Oettgen, P. et al. PDEF, a novel prostate epithelium-specific Ets transcription factor, interacts with the androgen receptor and activates prostate-specific antigen gene expression. J. Biol. Chem. 275, 1216–1225 (2000).
pubmed: 10625666
Rickman, D. S. et al. ERG-mediated alterations in chromatin conformation. Cancer Res. 72(4 Supplement), A31–A31 (2012).
Sood, A. K., Geradts, J. & Young, J. Prostate-derived Ets factor, an oncogenic driver in breast cancer. Tumor Biol. 39, 1010428317691688 (2017).
Takeda, D. Y. et al. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate. Cancer Cell. 174, 422–432 (2018).
Mansour, M. R. et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377 (2014).
pubmed: 25394790
pmcid: 4720521
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
pubmed: 24119843
Dekker, J. & Misteli, T. Long-range chromatin interactions. Cold Spring Harb. Perspect. Biol. 7, a019356 (2015).
pubmed: 26430217
pmcid: 4588061
Chung, S. et al. Association of a novel long non‐coding RNA in 8q24 with prostate cancer susceptibility. Cancer Sci. 102, 245–252 (2011).
pubmed: 20874843
Prensner, J. R. et al. The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc. Neoplasia 16, 900–8 (2014).
pubmed: 25425964
pmcid: 4240923
Liu, H. T., Fang, L., Cheng, Y. X. & Sun, Q. LncRNA PVT1 regulates prostate cancer cell growth by inducing the methylation of miR-146a. Cancer Med. 5, 3512–3519 (2016).
pubmed: 27794184
pmcid: 5224852
Meiners, J. et al. Upregulation of SPDEF is associated with poor prognosis in prostate cancer. Oncol. Lett. 18, 5107–5118 (2019).
pubmed: 31612022
pmcid: 6781494
van de Werken, H. J. et al. 4C technology: protocols and data analysis. Methods Enzymol. 513, 89–112 (2012).
pubmed: 22929766
Raviram, R. et al. 4C-ker: a method to reproducibly identify genome-wide interactions captured by 4C-Seq experiments. PLoS Comput. Biol. 12, e1004780 (2016).
pubmed: 26938081
pmcid: 4777514
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell. 38, 576–589 (2010).
pubmed: 20513432
pmcid: 2898526
Fabian, A. B. et al. Assigning roles to DNA regulatory motifs using comparative genomics. Bioinformatics 26, 860–866 (2010).
Durand, N. et al. Juicer provides a one-click system for analyzing loop-resolution Hi-C experiments. Cell Syst. 3, 95–98 (2016).
Campbell, P. J. et al. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
Davidson-Pilon, C. et al. CamDavidsonPilon/lifelines: v0.24.1 (Version v0.24.1) (Zenodo, 2020).
Wang, Q. et al. Unifying cancer and normal RNA sequencing data from different sources. Sci. Data 5, 180061 (2018).
pubmed: 29664468
pmcid: 5903355
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists. Nucleic Acids Res. 47, 191–98 (2019).
Supek, F. et al. REVIGO summarizes and visualizes long lists of gene ontology terms. PloS ONE 6, e21800 (2011).