@article{097f2500aac24af9894d4394fe9fe742,
title = "Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19",
abstract = "The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa. Transcription factor binding site remodeling by a risk allele for aggressive prostate cancer results in conversion of a promoter to an enhancer with downstream consequences on long noncoding RNA isoform expression and oncogenesis.",
keywords = "HNRNPAB, NKX3.1, PCAT19, YY1, bifunctional regulatory element, lncRNA, promoter-enhancer switching, prostate cancer progression, risk SNP, rs11672691",
author = "Hua, {Junjie Tony} and Musaddeque Ahmed and Haiyang Guo and Yuzhe Zhang and Sujun Chen and Fraser Soares and Jennifer Lu and Stanley Zhou and Miranda Wang and Hui Li and Larson, {Nicholas B.} and McDonnell, {Shannon K.} and Patel, {Parasvi S.} and Yi Liang and Yao, {Cindy Q.} and {van der Kwast}, Theodorus and Mathieu Lupien and Feng, {Felix Y.} and Amina Zoubeidi and Tsao, {Ming Sound} and Thibodeau, {Stephen N.} and Boutros, {Paul C.} and He, {Housheng Hansen}",
note = "Funding Information: The authors thank the Princess Margaret Genomic Centre for high-throughput sequencing support. The work was supported by the Princess Margaret Cancer Foundation ( 886012001223 to H.H.H.), Canada Foundation for Innovation and Ontario Research Fund ( CFI32372 to H.H.H.), NSERC discovery grant ( 498706 to H.H.H.), WICC Ontario 20th Anniversary Prostate Cancer Innovation Grant of the CCS ( 703800 to H.H.H.), CIHR operating grant ( 142246 to H.H.H.), Movember discovery grant ( D2016-1115 to H.H.H.) and Rising Star awards from Prostate Cancer Canada ( RS2014-01 to P.C.B. and RS2016-1022 to H.H.H.). H.H.H. holds a TFRI New Investigator Award, an OMIR Early Researcher Award, and a CIHR New Investigator Salary Award. J.T.H. is supported by the CIHR Graduate Student Doctoral Fellowship ( GSD146249 ). H.L. is supported by the Department of Defense (DOD) (grant W81XWH-17-1-0192 ). The results shown here are in whole or in part based upon data generated by the TCGA Research Network. Funding Information: The authors thank the Princess Margaret Genomic Centre for high-throughput sequencing support. The work was supported by the Princess Margaret Cancer Foundation (886012001223 to H.H.H.), Canada Foundation for Innovation and Ontario Research Fund (CFI32372 to H.H.H.), NSERC discovery grant (498706 to H.H.H.), WICC Ontario 20th Anniversary Prostate Cancer Innovation Grant of the CCS (703800 to H.H.H.), CIHR operating grant (142246 to H.H.H.), Movember discovery grant (D2016-1115 to H.H.H.) and Rising Star awards from Prostate Cancer Canada (RS2014-01 to P.C.B. and RS2016-1022 to H.H.H.). H.H.H. holds a TFRI New Investigator Award, an OMIR Early Researcher Award, and a CIHR New Investigator Salary Award. J.T.H. is supported by the CIHR Graduate Student Doctoral Fellowship (GSD146249). H.L. is supported by the Department of Defense (DOD) (grant W81XWH-17-1-0192). The results shown here are in whole or in part based upon data generated by the TCGA Research Network. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2018",
month = jul,
day = "26",
doi = "10.1016/j.cell.2018.06.014",
language = "English (US)",
volume = "174",
pages = "564--575.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}