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 TsaoStephen N. Thibodeau, Paul C. Boutros, Housheng Hansen He

Research output: Contribution to journalArticle

70 Scopus citations

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)
Pages (from-to)564-575.e18
JournalCell
Volume174
Issue number3
DOIs
StatePublished - Jul 26 2018

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hua, J. T., Ahmed, M., Guo, H., Zhang, Y., Chen, S., Soares, F., Lu, J., Zhou, S., Wang, M., Li, H., Larson, N. B., McDonnell, S. K., Patel, P. S., Liang, Y., Yao, C. Q., van der Kwast, T., Lupien, M., Feng, F. Y., Zoubeidi, A., ... He, H. H. (2018). Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19. Cell, 174(3), 564-575.e18. https://doi.org/10.1016/j.cell.2018.06.014