The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer
The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer
复制标题
lncRNA的转录格局揭示了LINC00511在ER阴性乳腺癌中的致癌功能
DOI：
10.1038/s41419-019-1835-3
复制
发表时间：
2019-08-08
影响因子：
9
通讯作者：
Pang, Da
中科院分区：
文献类型：
--
作者：
Zhang, Jian;Sui, Shiyao;Pang, Da
肿瘤分子特征的研究进展促进了从形态分类到基于分子特征的亚型的发展。随着转录组测序的深度和质量的进步，癌症特征的研究重点已经从编码蛋白质的基因扩展到非编码的RNA。在这里，我们根据癌症基因组图谱(TCGA)数据库中的乳腺癌亚型，研究了长非编码RNA(LncRNAs)的特征，以确定乳腺癌和雌激素受体(ER)阴性相关的LncRNAs队列。根据ER阴性相关LncRNAs变异的优先顺序，我们确定并研究了LINC00511在乳腺癌中的作用。我们确定LINC00511的高表达是乳腺癌患者不利的预后因素。此外，LINC00511还通过促进G1/S转换和抑制细胞凋亡而促进肿瘤生长。在转录水平上，ER缺乏直接影响转录因子AP-2(TFAP-2)激活的LINC00511在乳腺癌细胞中的表达。此外，机制研究表明，ER阴性相关的LINC00511与ZEST同源物2的增强子(EZH2，多梳抑制复合体2的催化亚单位，PRC2)相互作用，并招募PRC2介导组蛋白甲基化，促进CDKN1B在细胞核中的抑制。这一过程导致了ER阴性乳腺癌细胞生物学的改变。通过强调LINC00511的致癌功能，我们揭示了LncRNAs在ER阴性乳腺癌细胞周期调控网络中的作用，并建议开发LINC00511作为一种未来的抗癌治疗。
Advances in the molecular characteristics of cancers have facilitated the classification system from morphology to molecular characteristic-based subtypes. Cancer profiling has expanded in its focus from protein-coding genes to noncoding RNAs, with advances in the depth and quality of transcriptome sequencing. Here, we examined the profiles of long noncoding RNAs (lncRNAs) according to breast cancer subtype categories in The Cancer Genome Atlas (TCGA) database to identify a cohort of breast cancer- and oestrogen receptor (ER)-negative-associated lncRNAs. According to the prioritization of variation in ER-negative-associated lncRNAs, we identified and investigated the role of LINC00511 in breast cancer. We determined that high LINC00511 expression was an unfavourable prognostic factor for patients with breast cancer. Furthermore, LINC00511 promoted tumour growth by accelerating the G1/S transition and inhibiting apoptosis. At the transcriptional level, ER deficiency directly affected the expression of LINC00511 activated by transcription factor AP-2 (TFAP-2) in breast cancer cells. Moreover, mechanistic investigations demonstrated that ER-negative-associated LINC00511 interacted with enhancer of zeste homologue 2 (EZH2, the catalytic subunit of polycomb repressive complex 2, PRC2) and recruited PRC2 to mediate histone methylation, contributing to the repression of CDKN1B in the nucleus. This process resulted in altered ER-negative breast cancer cell biology. By highlighting the oncogenic function of LINC00511, we revealed the role of lncRNAs in regulating the network of cell cycle control in ER-negative breast cancer and suggested the exploitation of LINC00511 as an anticancer therapy in the future.