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 B 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; Stephen N Thibodeau; Paul C Boutros; Housheng Hansen He

doi:10.1016/j.cell.2018.06.014

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

Cell. 2018 Jul 26;174(3):564-575.e18. doi: 10.1016/j.cell.2018.06.014. Epub 2018 Jul 19.

Authors

Junjie Tony Hua¹, Musaddeque Ahmed², Haiyang Guo², Yuzhe Zhang³, Sujun Chen¹, Fraser Soares², Jennifer Lu⁴, Stanley Zhou¹, Miranda Wang², Hui Li⁵, Nicholas B Larson⁶, Shannon K McDonnell⁶, Parasvi S Patel¹, Yi Liang², Cindy Q Yao⁷, Theodorus van der Kwast⁸, Mathieu Lupien⁹, Felix Y Feng¹⁰, Amina Zoubeidi¹¹, Ming-Sound Tsao¹, Stephen N Thibodeau¹², Paul C Boutros¹³, Housheng Hansen He¹⁴

Affiliations

¹ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
² Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
³ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; College of Life Sciences, Central China Normal University, Wuhan, Hubei, China; College of Basic Medical Sciences, Dali University, Dali, Yunnan, China.
⁴ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁵ Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA.
⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁷ Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁸ Department of Pathology and Laboratory Medicine, Toronto General Hospital/University Health Network, Toronto, ON, Canada.
⁹ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
¹⁰ Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA; Department of Urology, University of California at San Francisco, San Francisco, CA, USA; Department of Medicine, University of California at San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
¹¹ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
¹² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
¹⁴ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada. Electronic address: hansenhe@uhnresearch.ca.

PMID: 30033362
DOI: 10.1016/j.cell.2018.06.014

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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alleles
Cell Line, Tumor
Enhancer Elements, Genetic / genetics
Gene Expression Regulation, Neoplastic / genetics
Gene Frequency / genetics
Genetic Predisposition to Disease / genetics
Homeodomain Proteins / metabolism
Humans
Male
Polymorphism, Single Nucleotide / genetics
Promoter Regions, Genetic / genetics
Prostatic Neoplasms / genetics*
Protein Binding
RNA Isoforms / genetics
RNA, Long Noncoding / genetics*
Risk Factors
Transcription Factors / metabolism
YY1 Transcription Factor / metabolism

Substances

Homeodomain Proteins
NKX3-1 protein, human
RNA Isoforms
RNA, Long Noncoding
Transcription Factors
YY1 Transcription Factor
YY1 protein, human

Grants and funding

142246/CIHR/Canada