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 language | English (US) |
|---|---|
| Journal | Cell |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
Fingerprint
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
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 journal › Article
}
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 -