Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

Sylvan C. Baca, David Y. Takeda, Ji-heui Seo, Justin Hwang, Sheng Yu Ku, Rand Arafeh, Taylor Arnoff, Supreet Agarwal, Connor Bell, Edward O’connor, Xintao Qiu, Sarah Abou Alaiwi, Rosario I. Corona, Marcos A. S. Fonseca, Claudia Giambartolomei, Paloma Cejas, Klothilda Lim, Monica He, Anjali Sheahan, Amin NassarJacob E. Berchuck, Lisha Brown, Holly M. Nguyen, Ilsa M. Coleman, Arja Kaipainen, Navonil De Sarkar, Peter S. Nelson, Colm Morrissey, Keegan Korthauer, Mark M. Pomerantz, Leigh Ellis, Bogdan Pasaniuc, Kate Lawrenson, Kathleen Kelly, Amina Zoubeidi, William C. Hahn, Himisha Beltran, Henry W. Long, Myles Brown, Eva Corey, Matthew L. Freedman

Research output: Contribution to journalArticlepeer-review


Lineage 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.

Original languageEnglish (US)
Article number1979
JournalNature communications
Issue number1
StatePublished - Mar 30 2021

Bibliographical note

Funding Information:
This work was supported by the PNW Prostate Cancer SPORE P50 CA097186, DOD W81XWH-19-1-0565, DOD W81XWH-17-1-0415, P01 CA163227, R01 CA193910, R01 CA233863, The Prostate Cancer Foundation, The PhRMA Foundation, The Richard M. Lucas Foundation, the European Union’s Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie grant agreement No. 754490, the National Cancer Institute (T32CA009172), and by Rebecca and Nathan Milikowsky. We would like to thank the patients who generously donated tissue that made this research possible.

Publisher Copyright:
© 2021, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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