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

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

doi:10.1038/s41467-021-22139-7

Abstract

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.

Highlights

Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer
We identified 14,985 sites with eight-fold or greater increases in H3K27 acetylation in neuroendocrine prostate cancer (NEPC) compared to prostate adenocarcinoma (PRAD) at an adjusted p-value of 10−3
In summary, our work demonstrates that the cis-regulatory landscape of prostate cancer is extensively reprogrammed in NEPC

Summary

Introduction

The ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. 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). 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. 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. We profile histone modifications in NEPC and PRAD patient-derived xenografts (PDXs), identifying ~15,000 regulatory elements that are dormant in PRAD but consistently activated in NEPC. Our data indicate a dependency of NEPC upon FOXA1, which may have therapeutic implications

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Conclusion