Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. However, mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei is a distinguishing histopathological feature of NEPC, we identified 36 heterochromatin-related genes that are significantly enriched in NEPC by transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression is increased early and steadily during NEPC development and remain elevated in the developed NEPC tumor. Its elevated expression is further confirmed in multiple PDX and clinical NEPC samples. Functional studies showed that HP1α knockdown in the NCI-H660 NEPC cell line dramatically inhibits proliferation, completely ablates colony formation, and induces apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promotes NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduces expression of androgen receptor (AR) and RE1 silencing transcription factor (REST), two crucial transcription factors silenced in NEPC, and enriches the repressive histone mark trimethylation of histone H3 at Lys9 (H3K9me3) on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and/or management.

Citation Format: Xinpei Ci, Jun Hao, Xin Dong, Stephen Y. Choi, Hui Xue, Sifeng Qu, Ladan Fazli, Francesco Crea, Christopher Ong, Amina Zoubeidi, Housheng H. He, Martin E. Gleave, Colin C. Collins, Dong Lin, Yuzhuo Wang. A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 773.