Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19

Junjie Tony Hua, Musaddeque Ahmed, Haiyang Guo, Yuzhe Zhang, Sujun Chen, Fraser Soares, Jennifer Lu, Stanley Zhou, Miranda Wang, Hui Li, Nicholas Larson, Shannon K. McDonnell, Parasvi S. Patel, Yi Liang, Cindy Q. Yao, Theodorus van der Kwast, Mathieu Lupien, Felix Y. Feng, Amina Zoubeidi, Ming Sound Tsao & 3 others Stephen N Thibodeau, Paul C. Boutros, Housheng Hansen He

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
JournalCell
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Long Noncoding RNA
Single Nucleotide Polymorphism
Prostatic Neoplasms
YY1 Transcription Factor
Protein Isoforms
Transcription Factors
RNA Isoforms
cdc Genes
Introns
Tumors
Carcinogenesis
Genes
Alleles
Binding Sites
Cells
Neoplasm Metastasis
Growth

Keywords

  • bifunctional regulatory element
  • HNRNPAB
  • lncRNA
  • NKX3.1
  • PCAT19
  • promoter-enhancer switching
  • prostate cancer progression
  • risk SNP
  • rs11672691
  • YY1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hua, J. T., Ahmed, M., Guo, H., Zhang, Y., Chen, S., Soares, F., ... He, H. H. (Accepted/In press). Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19. Cell. https://doi.org/10.1016/j.cell.2018.06.014

Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19. / Hua, Junjie Tony; Ahmed, Musaddeque; Guo, Haiyang; Zhang, Yuzhe; Chen, Sujun; Soares, Fraser; Lu, Jennifer; Zhou, Stanley; Wang, Miranda; Li, Hui; Larson, Nicholas; McDonnell, Shannon K.; Patel, Parasvi S.; Liang, Yi; Yao, Cindy Q.; van der Kwast, Theodorus; Lupien, Mathieu; Feng, Felix Y.; Zoubeidi, Amina; Tsao, Ming Sound; Thibodeau, Stephen N; Boutros, Paul C.; He, Housheng Hansen.

In: Cell, 01.01.2018.

Research output: Contribution to journalArticle

Hua, JT, Ahmed, M, Guo, H, Zhang, Y, Chen, S, Soares, F, Lu, J, Zhou, S, Wang, M, Li, H, Larson, N, McDonnell, SK, Patel, PS, Liang, Y, Yao, CQ, van der Kwast, T, Lupien, M, Feng, FY, Zoubeidi, A, Tsao, MS, Thibodeau, SN, Boutros, PC & He, HH 2018, 'Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19', Cell. https://doi.org/10.1016/j.cell.2018.06.014
Hua, Junjie Tony ; Ahmed, Musaddeque ; Guo, Haiyang ; Zhang, Yuzhe ; Chen, Sujun ; Soares, Fraser ; Lu, Jennifer ; Zhou, Stanley ; Wang, Miranda ; Li, Hui ; Larson, Nicholas ; McDonnell, Shannon K. ; Patel, Parasvi S. ; Liang, Yi ; Yao, Cindy Q. ; van der Kwast, Theodorus ; Lupien, Mathieu ; Feng, Felix Y. ; Zoubeidi, Amina ; Tsao, Ming Sound ; Thibodeau, Stephen N ; Boutros, Paul C. ; He, Housheng Hansen. / Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19. In: Cell. 2018.
@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 = "bifunctional regulatory element, HNRNPAB, lncRNA, NKX3.1, PCAT19, promoter-enhancer switching, prostate cancer progression, risk SNP, rs11672691, YY1",
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 Nicholas Larson 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}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.cell.2018.06.014",
language = "English (US)",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",

}

TY - JOUR

T1 - Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19

AU - Hua, Junjie Tony

AU - Ahmed, Musaddeque

AU - Guo, Haiyang

AU - Zhang, Yuzhe

AU - Chen, Sujun

AU - Soares, Fraser

AU - Lu, Jennifer

AU - Zhou, Stanley

AU - Wang, Miranda

AU - Li, Hui

AU - Larson, Nicholas

AU - McDonnell, Shannon K.

AU - Patel, Parasvi S.

AU - Liang, Yi

AU - Yao, Cindy Q.

AU - van der Kwast, Theodorus

AU - Lupien, Mathieu

AU - Feng, Felix Y.

AU - Zoubeidi, Amina

AU - Tsao, Ming Sound

AU - Thibodeau, Stephen N

AU - Boutros, Paul C.

AU - He, Housheng Hansen

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - bifunctional regulatory element

KW - HNRNPAB

KW - lncRNA

KW - NKX3.1

KW - PCAT19

KW - promoter-enhancer switching

KW - prostate cancer progression

KW - risk SNP

KW - rs11672691

KW - YY1

UR - http://www.scopus.com/inward/record.url?scp=85049332189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049332189&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.06.014

DO - 10.1016/j.cell.2018.06.014

M3 - Article

JO - Cell

JF - Cell

SN - 0092-8674

ER -