Oral Presentation Epigenetics 2013

The Estrogen receptor alpha regulated NEAT1 long non-coding RNA promotes prostate cancer progression (#3)

Mark A Rubin 1 2 , Dimple Chakravarty 1 , Andrea Sboner 1 2 3 , Sujit S Nair 4 , Eugenia Giannopoulou 3 , Rouhan Li 5 , Sven Henning 6 , Juan M Mosquera 1 , Kyung Park 1 , Myriam Kossai 1 , Nicholas Erho 7 , Ismael A Vergara 7 , Mercedeyh Ghadessi 7 , Elai Davicioni 7 , Robert B Jenkins 8 , Nallasivam Palanisamy 9 , Zhengming Chen 10 , Shinici Nakagawa 11 , Tetsuro Hirose 12 , Neil H Bander 13 , Himisha Beltran 1 2 , Archa H Fox 5 , Olivier Elemento 2 3
  1. Department of Pathology & Laboratory Medicine , Weill Cornell Medical College, New York, NY , USA
  2. Institute for Precision Medicine, Weill Medical College of Cornell University & New York Presbyterian Hospital, New York, USA
  3. Institute for Computational Medicine , Weill Cornell Medical College, New York, NY, USA
  4. Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences,, George Washington University , Washington , DC, USA
  5. School of Biomedical, Biomolecular, and Chemical Sciences, University of Western Australia, Perth, WA, Australia
  6. Chemical Genomics Centre, Dormund, Germany
  7. Research and Development, GenomeDx Biosciences, Vancouver, British Columbia, Canada
  8. Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
  9. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
  10. Division of Biostatistics and Epidemiology Department of Public Health, Weill Cornell Medical College, NY, USA
  11. RNA Biology Laboratory, RIKEN Advanced Research Institute, Saitama, Japan
  12. Functional RNomics Team, Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan
  13. Department of Urology, Weill Cornell Medical College of Cornell University , NY, USA

Prostate cancer predominantly exhibits androgen dependence but recent studies indicate that estrogen receptor signaling is also involved in its development although the molecular mechanism remains poorly understood. By integrating ChIP and RNA-sequencing pipelines, we analyzed functional consequences of estrogen receptor binding and influence on the prostate cancer transcriptome. We found that ERa specifically regulates a subset of non-coding transcriptome in prostate cancer and nominated NEAT1 long non-coding RNA (lncRNA) as a downstream mediator of ERa signaling. ERa-NEAT1 axis was refractile to androgen receptor (AR) or AR antagonists. NEAT1 promoted prostate tumorigenesis by generating an epigenetic “on” state of downstream prostate cancer specific signature genes. NEAT1 expression positively correlated with PSMA in prostate adenocarcinoma and with B3GAT1 in neuroendocrine prostate cancer. Analysis of a large clinical cohort suggested that NEAT1 is a novel prognostic biomarker of clinically aggressive disease. NEAT1 overexpression is also potentially a predictive biomarker of patients with advanced prostate cancer who might benefit from co-targeting ERa and AR. In summary, our studies show that prostate cancer cells adapt to an alternate ERa-NEAT1 axis for survival and therapy resistance.