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Updated: Nov 11, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
Sylvan C Baca1,2,3, David Y Takeda4, Ji-Heui Seo1,3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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.
Insights
Lineage plasticity drives cancer therapy resistance. Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma (PRAD) via epigenomic reprogramming, with FOXA1 crucial for NEPC proliferation and gene expression.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Lineage plasticity is a key mechanism of adaptive resistance to cancer therapies.
- Neuroendocrine prostate cancer (NEPC) develops from prostate adenocarcinoma (PRAD) under androgen signaling inhibition.
- NEPC is an aggressive subtype characterized by neuroendocrine gene expression and androgen independence.
Purpose of the Study:
- To investigate the epigenomic underpinnings of NEPC development and resistance.
- To identify regulatory elements and transcription factors involved in NEPC lineage plasticity.
Main Methods:
- Chromatin immunoprecipitation and sequencing (ChIP-seq) to profile histone modifications in NEPC and PRAD patient-derived xenografts (PDXs).
- Analysis of cis-regulatory elements and transcription factor binding.
- Experimental manipulation of NE lineage transcription factors (ASCL1, NKX2-1) in PRAD cells.
Main Results:
- Identification of approximately 15,000 cis-regulatory elements recurrently activated in NEPC.
- Reprogramming of the FOXA1 transcription factor to NE-specific regulatory elements in NEPC.
- Demonstration that FOXA1 is essential for NEPC proliferation and neuroendocrine gene expression, even without androgen receptor (AR) dependence.
- Ectopic expression of ASCL1 and NKX2-1 reprograms FOXA1 binding and induces enhancer activity in PRAD cells.
Conclusions:
- FOXA1 plays a critical role in NEPC lineage maintenance and proliferation.
- Epigenomic profiling is a valuable approach for identifying cancer dependencies.
- Understanding lineage plasticity mechanisms can reveal new therapeutic strategies for aggressive prostate cancer.
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