Prostate cancer reactivates developmental epigenomic programs during metastatic progression.

Nature Genetics
Mark M PomerantzMatthew L Freedman

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.

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Citations

Sep 19, 2020·Protein & Cell·Mona TengHousheng Hansen He
Dec 3, 2020·The New England Journal of Medicine·Wadih ArapJoseph F Costello
Jan 23, 2021·Science·Gary ReynoldsMuzlifah Haniffa
Jan 23, 2021·Differentiation; Research in Biological Diversity·Gail S Prins
Mar 5, 2021·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Jamal Majidpoor, Keywan Mortezaee
Dec 29, 2020·Molecular Aspects of Medicine·Isabel Mayayo-PeraltaWilbert Zwart
Apr 1, 2021·European Urology·Anbarasu KumaraswamyJoshi J Alumkal
May 14, 2021·Nature Communications·Sergey AbramovIvan V Kulakovskiy
Jun 9, 2021·The Journal of Clinical Investigation·Yundong HeHaojie Huang
Jul 1, 2021·Cell Biology International·Keywan Mortezaee
Jun 20, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dae-Hwan KimJoshi J Alumkal
Aug 30, 2021·Clinical Epigenetics·Romina SilvaAntoinette S Perry
Sep 15, 2021·The Biochemical Journal·Jocelyn F Chen, Qin Yan
Sep 14, 2021·Frontiers in Cell and Developmental Biology·Tao WangJinjian Yang
Sep 24, 2021·Science·Toshikazu UshijimaPatrick Tan
Oct 3, 2021·Nature Communications·Tore BleckwehlÁlvaro Rada-Iglesias

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Methods Mentioned

BETA
xenografts
biopsy
immunoprecipitation
biopsies
PCA
acetylation
HiChIP
xenograft
PCR
RNA-seq

Software Mentioned

HOMER
QuantStudio
R
rtracklayer Bioconductor
rpart
dmrseq Bioconductor
DEseq2
multiBigwigSummary
ChromHMM
deepTools

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