Novel lncRNA LINC00844 Regulates Prostate Cancer Cell Migration and Invasion through AR Signaling
Novel lncRNA LINC00844 Regulates Prostate Cancer Cell Migration and Invasion through AR Signaling
复制标题
DOI：
10.1158/1541-7786.mcr-18-0087
复制
发表时间：
2018-12-01
影响因子：
5.2
通讯作者：
Cheung, Edwin
中科院分区：
文献类型：
--
作者：
Lingadahalli, Shreyas;Jadhao, Sudhir;Cheung, Edwin
人类基因组大部分是转录的，产生了丰富的非编码转录物库，这些转录物参与了包括癌症在内的无数生物过程。然而，有多少非编码转录物如长非编码RNA（lncRNA）在癌症中起作用仍不清楚。这项研究确定了一组新的临床相关的雄激素调节的lncRNA在前列腺癌。在这组中，LINC00844被证明是一个直接的雄激素调节的目标，在雄激素受体（AR）依赖性前列腺癌细胞中积极转录。LINC00844在正常前列腺中的表达高于恶性和转移性前列腺癌临床标本，低表达患者预后差，生化复发率显著增加，提示LINC00844具有抑制肿瘤进展和转移的功能。事实上，体外功能丧失研究显示，LINC00844可防止前列腺癌细胞迁移和侵袭。此外，基因表达谱分析的结果表明，LINC00844以反式方式发挥作用，影响全局雄激素调节的基因转录。机制证据显示LINC00844在促进AR与染色质结合方面是重要的。最后，LINC00844部分通过激活NDRG1（一种关键的癌症转移抑制因子）的表达来介导其表型效应。总的来说，LINC00844是一种新的AR的coregulator，在雄激素转录网络和前列腺癌的发展和进展中发挥着重要作用。影响：这项研究强调了lncRNA，LINC00844，在调节全球AR调节基因在前列腺癌中的作用，通过调节AR结合染色质。(C)2018年AACR。
The human genome is mostly transcribed, yielding a rich repository of noncoding transcripts that are involved in a myriad of biological processes including cancer. However, how many noncoding transcripts such as long noncoding RNAs (lncRNA) function in cancer is still unclear. This study identified a novel set of clinically relevant androgen-regulated lncRNAs in prostate cancer. Among this group, LINC00844 was demonstrated to be a direct androgen-regulated target that is actively transcribed in androgen receptor (AR)-dependent prostate cancer cells. The expression of LINC00844 is higher in normal prostate compared with malignant and metastatic prostate cancer clinical specimens, and patients with low expression had a poor prognosis and significantly increased biochemical recurrence, suggesting LINC00844 functions in suppressing tumor progression and metastasis. Indeed, in vitro loss-of-function studies revealed that LINC00844 prevents prostate cancer cell migration and invasion. Moreover, findings from gene expression profiling analysis indicated that LINC00844 functions in trans, affecting global androgen-regulated gene transcription. Mechanistic evidence reveals that LINC00844 is important in facilitating AR binding to the chromatin. Finally, LINC00844 mediates its phenotypic effects in part by activating the expression of NDRG1, a crucial cancer metastasis suppressor. Collectively, LINC00844 is a novel coregulator of AR that plays a central role in the androgen transcriptional network and the development and progression of prostate cancer.Implications: This study highlights the function of the lncRNA, LINC00844, in regulating global AR-regulated genes in prostate cancer by modulating AR binding to chromatin. (C) 2018 AACR.