Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers

作者：Zhang, Yan; Zheng, Dayong; Zhou, Ting; Song, Haiping; Hulsurkar, Mohit; Su, Ning; Liu, Ying; Wang, Zheng; Shao, Long; Ittmann, Michael; Gleave, Martin; Han, Huanxing; Xu, Feng; Liao, Wangjun; Wang, Hongbo; Li, Wenliang^*

来源：Nature Communications, 2018, 9(1): 4080.

DOI：10.1038/s41467-018-06177-2

• TUMOR-GROWTH
• ANTIANDROGEN RESISTANCE
• LINEAGE PLASTICITY
• BETA-BLOCKERS
• NUDE-MICE
• CELLS
• EZH2
• POLYCOMB
• PROGRESSION
• EXPRESSION

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.

• 出版日期2018-10-4
• 单位南方医科大学中西医结合医院; 华中科技大学; 广州市胸科医院; 南方医科大学; 中南大学; 天津市中医药研究院附属医院