Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
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Published:2021-03-30
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Baca Sylvan C., Takeda David Y., Seo Ji-Heui, Hwang Justin, Ku Sheng YuORCID, Arafeh Rand, Arnoff Taylor, Agarwal SupreetORCID, Bell Connor, O’Connor Edward, Qiu XintaoORCID, Alaiwi Sarah AbouORCID, Corona Rosario I., Fonseca Marcos A. S., Giambartolomei ClaudiaORCID, Cejas Paloma, Lim Klothilda, He Monica, Sheahan Anjali, Nassar AminORCID, Berchuck Jacob E.ORCID, Brown Lisha, Nguyen Holly M., Coleman Ilsa M., Kaipainen Arja, De Sarkar Navonil, Nelson Peter S.ORCID, Morrissey Colm, Korthauer Keegan, Pomerantz Mark M., Ellis LeighORCID, Pasaniuc Bogdan, Lawrenson KateORCID, Kelly Kathleen, Zoubeidi AminaORCID, Hahn William C.ORCID, Beltran HimishaORCID, Long Henry W.ORCID, Brown Myles, Corey EvaORCID, Freedman Matthew L.ORCID
Abstract
AbstractLineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.
Funder
U.S. Department of Health & Human Services | National Institutes of Health U.S. Department of Defense Prostate Cancer Foundation Pharmaceutical Research and Manufacturers of America Foundation U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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