风险 SNP 介导的启动子-增强子转换通过 lncRNA PCAT19 驱动前列腺癌。
Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19.
机构信息
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
出版信息
Cell. 2018 Jul 26;174(3):564-575.e18. doi: 10.1016/j.cell.2018.06.014. Epub 2018 Jul 19.
The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa.
前列腺癌（PCa）风险相关 SNP rs11672691 与诊断时侵袭性疾病呈正相关。我们表明，rs11672691 位于长非编码 RNA PCAT19 的短亚型（PCAT19-short）启动子上，PCAT19-short 位于长亚型（PCAT19-long）的第三个内含子中。风险变体分别与 PCAT19-short 和 PCAT19-long 的水平降低和增加相关。从机制上讲，风险 SNP 区域具有启动子和增强子的双重功能。rs11672691 的风险变体及其 LD SNP rs887391 降低了转录因子 NKX3.1 和 YY1 与 PCAT19-short 启动子的结合，导致启动子较弱但增强子活性较强，从而激活 PCAT19-long。PCAT19-long 与 HNRNPAB 相互作用，激活与 PCa 进展相关的一组细胞周期基因，从而促进 PCa 肿瘤的生长和转移。总之，这些发现揭示了风险 SNP 介导的启动子-增强子转换机制，该机制是侵袭性 PCa 起始和进展的基础。
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