Journal Article

Prostate cancer reactivates developmental epigenomic programs during metastatic progression

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

2020

Overview

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. Analyses of epigenomic datasets spanning transitions from normal prostate epithelium to localized prostate cancer to metastases show that latent developmental programs are reactivated in metastatic disease and that prostate lineage-specific regulatory elements are strongly enriched for prostate cancer risk heritability.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/177 / 631/67/322 / 631/67/589/466 / Agriculture / Androgen receptors / Androgens / Animal Genetics and Genomics / Binding sites / Biology / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer Research / Cell Line / Cell Line, Tumor / Datasets / Deoxyribonucleic acid / Development and progression / Disease Progression / DNA / DNA binding proteins / Enhancers / Epigenetic inheritance / Epigenetics / Epigenomics - methods / Epithelium / Gene expression / Gene Expression Regulation, Neoplastic - genetics / Gene Function / Genomes / HEK293 Cells / Hepatocyte Nuclear Factor 3-alpha - genetics / Heritability / Human Genetics / Human tissues / Humans / Male / Metastases / Metastasis / Mutation / Ontology / Organogenesis / Principal components analysis / Prostate - pathology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Receptors, Androgen - genetics / Regulatory sequences / Regulatory Sequences, Nucleic Acid - genetics / Transcription factors / Tumors