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

被引：260

作者：

Hua, Junjie Tony ^{[1
,2
]}

Ahmed, Musaddeque ^{[1
]}

Guo, Haiyang ^{[1
]}

Zhang, Yuzhe ^{[1
,3
,4
]}

Chen, Sujun ^{[1
,2
]}

Soares, Fraser ^{[1
]}

Lu, Jennifer ^{[1
,5
]}

Zhou, Stanley ^{[1
,2
]}

Wang, Miranda ^{[1
]}

Li, Hui ^{[6
]}

Larson, Nicholas B. ^{[7
]}

McDonnell, Shannon K. ^{[7
]}

Patel, Parasvi S. ^{[1
,2
]}

Liang, Yi ^{[1
]}

Yao, Cindy Q. ^{[8
]}

van der Kwast, Theodorus ^{[9
]}

Lupien, Mathieu ^{[1
,2
,8
]}

Feng, Felix Y. ^{[10
,11
,12
]}

Zoubeidi, Amina ^{[13
]}

Tsao, Ming-Sound ^{[1
,2
]}

Thibodeau, Stephen N. ^{[14
]}

Boutros, Paul C. ^{[2
,8
,15
]}

He, Housheng Hansen ^{[1
,2
]}

机构：

[1] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G IL7, Canada

[2] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[3] Cent China Normal Univ, Coll Life Sci, Wuhan, Hubei, Peoples R China

[4] Dali Univ, Coll Basic Med Sci, Dali, Yunnan, Peoples R China

[5] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S IA1, Canada

[6] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA

[7] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[8] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[9] Univ Hlth Network, Toronto Gen Hosp, Dept Pathol & Lab Med, Toronto, ON, Canada

[10] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA

[11] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[12] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[13] Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada

[14] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[15] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada

来源：

CELL | 2018年 / 174卷 / 03期

基金：

加拿大自然科学与工程研究理事会; 加拿大创新基金会;

关键词：

POTENTIAL THERAPEUTIC TARGET; LONG NONCODING RNAS; SUSCEPTIBILITY LOCI; ANDROGEN RECEPTOR; CELL-CYCLE; INTEGRATIVE ANALYSIS; GENE; EXPRESSION; NKX3.1; PROGRESSION;

D O I：

10.1016/j.cell.2018.06.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：564 / +

页数：30

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