Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод в очереди
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Baca Sylvan C, Takeda David Y, Seo Ji-Heui, Hwang Justin, Ku Sheng Yu, Arafeh Rand, Arnoff Taylor, Agarwal Supreet, Bell Connor, O'Connor Edward, Qiu Xintao, Alaiwi Sarah Abou, Corona Rosario I, Fonseca Marcos A S, Giambartolomei Claudia, Cejas Paloma, Lim Klothilda, He Monica, Sheahan Anjali, Nassar Amin, Berchuck Jacob E, Brown Lisha, Nguyen Holly M, Coleman Ilsa M, Kaipainen Arja, De Sarkar Navonil, Nelson Peter S, Morrissey Colm, Korthauer Keegan, Pomerantz Mark M, Ellis Leigh, Pasaniuc Bogdan, Lawrenson Kate, Kelly Kathleen, Zoubeidi Amina, Hahn William C, Beltran Himisha, Long Henry W, Brown Myles, Corey Eva, Freedman Matthew L
Аннотация
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.