Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Mark M. Pomerantz, Xintao Qiu, Yanyun Zhu, David Y. Takeda, Wenting Pan, Sylvan C. Baca, Alexander Gusev, Keegan D. Korthauer, Tesa M. Severson, Gavin Ha, Srinivas R. Viswanathan, Ji Heui Seo, Holly M. Nguyen, Baohui Zhang, Bogdan Pasaniuc, Claudia Giambartolomei, Sarah A. Alaiwi, Connor A. Bell, Edward P. O’Connor, Matthew S. ChabotDavid R. Stillman, Rosina Lis, Alba Font-Tello, Lewyn Li, Paloma Cejas, Andries M. Bergman, Joyce Sanders, Henk G. van der Poel, Simon A. Gayther, Kate Lawrenson, Marcos A.S. Fonseca, Jessica Reddy, Rosario I. Corona, Gleb Martovetsky, Brian Egan, Toni Choueiri, Leigh Ellis, Isla P. Garraway, Gwo Shu Mary Lee, Eva Corey, Henry W. Long, Wilbert Zwart, Matthew L. Freedman

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Original languageEnglish
Pages (from-to)790-799
Number of pages10
JournalNature Genetics
Volume52
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

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    Pomerantz, M. M., Qiu, X., Zhu, Y., Takeda, D. Y., Pan, W., Baca, S. C., Gusev, A., Korthauer, K. D., Severson, T. M., Ha, G., Viswanathan, S. R., Seo, J. H., Nguyen, H. M., Zhang, B., Pasaniuc, B., Giambartolomei, C., Alaiwi, S. A., Bell, C. A., O’Connor, E. P., ... Freedman, M. L. (2020). Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nature Genetics, 52(8), 790-799. https://doi.org/10.1038/s41588-020-0664-8