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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 B; 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.
Afiliação
  • Hua JT; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • Ahmed M; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Guo H; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Zhang Y; 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.
  • Chen S; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • Soares F; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Lu J; 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.
  • Zhou S; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • Wang M; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Li H; Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA.
  • Larson NB; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • McDonnell SK; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Patel PS; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • Liang Y; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Yao CQ; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
  • van der Kwast T; Department of Pathology and Laboratory Medicine, Toronto General Hospital/University Health Network, Toronto, ON, Canada.
  • Lupien M; 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.
  • Feng FY; 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 Famil
  • Zoubeidi A; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Tsao MS; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • Thibodeau SN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Boutros PC; 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.
  • He HH; 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.
Cell ; 174(3): 564-575.e18, 2018 07 26.
Article em En | MEDLINE | ID: mdl-30033362
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / RNA Longo não Codificante Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Humans / Male Idioma: En Revista: Cell Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / RNA Longo não Codificante Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Humans / Male Idioma: En Revista: Cell Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Canadá