Faculty Collaboration Database

Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer. Nat Commun 2021 Mar 30;12(1):1979

Date

04/01/2021

Pubmed ID

33785741

Pubmed Central ID

PMC8010057

DOI

10.1038/s41467-021-22139-7

Scopus ID

2-s2.0-85103682911 (requires institutional sign-in at Scopus site)   58 Citations

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.

Author List

Baca SC, Takeda DY, Seo JH, Hwang J, Ku SY, Arafeh R, Arnoff T, Agarwal S, Bell C, O'Connor E, Qiu X, Alaiwi SA, Corona RI, Fonseca MAS, Giambartolomei C, Cejas P, Lim K, He M, Sheahan A, Nassar A, Berchuck JE, Brown L, Nguyen HM, Coleman IM, Kaipainen A, De Sarkar N, Nelson PS, Morrissey C, Korthauer K, Pomerantz MM, Ellis L, Pasaniuc B, Lawrenson K, Kelly K, Zoubeidi A, Hahn WC, Beltran H, Long HW, Brown M, Corey E, Freedman ML

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Cell Line, Tumor
Disease Progression
Epigenomics
Gene Expression Regulation, Neoplastic
Hepatocyte Nuclear Factor 3-alpha
Humans
Male
Mutation
Neuroendocrine Tumors
Prostatic Neoplasms
RNA Interference
Receptors, Androgen