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前列腺癌转移时可重激活发育表观程序
作者:小柯机器人 发布时间:2020/7/22 22:45:32

美国哈佛医学院Matthew L. Freedman、荷兰癌症研究所Wilbert Zwart等研究人员合作发现,前列腺癌在转移过程中重激活发育表观基因组程序。这一研究成果于2020年7月20日在线发表在《自然—遗传学》上。

研究人员表示,表观遗传过程调控前列腺癌(PCa)发展,例如PCa细胞依赖于雄激素受体(AR,一种前列腺的核心转录因子)。

研究人员从来自人体组织的标本中生成了268个表观基因组数据集,其涵盖从正常前列腺上皮到局部PCa再到转移的状态转换。研究人员发现转移PCa中的AR位点重编程不是从头创建的,相反,它们是由正常前列腺上皮细胞中的转录因子FOXA1和HOXB13预先生成的。

转移性肿瘤中的重编程调节元件劫持了潜在的发育程序,从而调控了与前列腺器官发生有关的位点。重激活调节元件的分析能够鉴定和验证HOXB13、FOXA1和NKX3-1的转移特异性增强子。

最后,研究人员观察到前列腺谱系特异性调控元件与PCa风险遗传力和体细胞突变密度密切相关。因此,通过表观基因组学研究前列腺生物学是了解肿瘤进展机制的基础。

附:英文原文

Title: Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Author: Mark M. Pomerantz, Xintao Qiu, Yanyun Zhu, David Y. Takeda, Wenting Pan, Sylvan C. Baca, Alexander Gusev, Keegan D. Korthauer, Tesa M. Severson, Gavin Ha, Srinivas R. Viswanathan, Ji-Heui Seo, Holly M. Nguyen, Baohui Zhang, Bogdan Pasaniuc, Claudia Giambartolomei, Sarah A. Alaiwi, Connor A. Bell, Edward P. OConnor, Matthew S. Chabot, David R. Stillman, Rosina Lis, Alba Font-Tello, Lewyn Li, Paloma Cejas, Andries M. Bergman, Joyce Sanders, Henk G. van der Poel, Simon A. Gayther, Kate Lawrenson, Marcos A. S. Fonseca, Jessica Reddy, Rosario I. Corona, Gleb Martovetsky, Brian Egan, Toni Choueiri, Leigh Ellis, Isla P. Garraway, Gwo-Shu Mary Lee, Eva Corey, Henry W. Long, Wilbert Zwart, Matthew L. Freedman

Issue&Volume: 2020-07-20

Abstract: Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

DOI: 10.1038/s41588-020-0664-8

Source: https://www.nature.com/articles/s41588-020-0664-8

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex