Long noncoding RNA PART1 restrains aggressive gastric cancer through the epigenetic silencing of PDGFBviathe PLZF-mediated recruitment of EZH2
Long noncoding RNA PART1 restrains aggressive gastric cancer through the epigenetic silencing of PDGFBviathe PLZF-mediated recruitment of EZH2
复制标题
长非编码 RNA PART1 通过 PLZF 介导的 EZH2 募集导致 PDGFB 表观遗传沉默，从而抑制侵袭性胃癌
DOI：
10.1038/s41388-020-01442-5
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发表时间：
2020-09-08
期刊：
影响因子：
8
通讯作者：
Ji, J.
中科院分区：
文献类型：
--
作者：
Han, H.;Wang, S.;Ji, J.
目前的报道提到长非编码RNA（lncRNA）前列腺雄激素调节转录本1（PART1）在某些类型的癌症中作为肿瘤抑制因子，但在其他类型的癌症中作为癌基因的作用。据报道，在胃癌中，它被下调。然而，PART1功能在胃癌中的临床意义和潜在机制仍不清楚。在这里，七个差异表达水平的非编码RNA（DE-lncRNA）筛选胃癌通过探针重新注释的人外显子阵列。选择PART1进行进一步研究，因为其倍数变化数较高。在我们的队列中，PART1通过qPCR和原位杂交（ISH）被鉴定为胃癌组织中显著下调的lncRNA，其低表达与术后转移和术后总生存时间短显著相关。通过功能获得实验的结果，PART1被证实为肿瘤抑制因子，其不仅可以在体外降低细胞活力、迁移和侵袭，而且可以在体内降低肿瘤发生和肿瘤转移。RNA pull-down和RNA结合蛋白免疫沉淀（RIP）显示PART1与雄激素受体（AR）相互作用，然后，早幼粒细胞白血病锌指（PLZF）以雄激素非依赖性方式上调。在链式反应中，染色质免疫沉淀（ChIP）试验还表明，PLZF上调增加了血小板衍生生长因子（PDGFB）启动子中EZH 2和H3 K27三甲基化的富集，从而抑制PDGFB和随后的PDGFRβ/PI 3 K/Akt信号传导途径。基于这些发现，我们发现PART1通过促进PLZF表达，随后募集EZH 2介导表观遗传PDGFB沉默和下游PI 3 K/Akt抑制来发挥肿瘤抑制作用，表明PART1在抑制GC细胞的侵袭能力方面具有关键作用，并为GC进展中的lncRNA提供了新的视角。
Current reports refer to the role of long noncoding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) as a tumor suppressor in some types of cancer but as an oncogene in other kinds of cancer. In gastric cancer, it had been reported to be downregulated. However, the clinical significance and underlying mechanism of PART1 function in gastric cancer remains undefined. Here, seven differential expression levels of noncoding RNAs (DE-lncRNAs) were screened from gastric cancer through a probe reannotation of a human exon array. PART1 was selected for further study because of its high fold change number. In our cohort, PART1 was identified as a significant downregulated lncRNA in gastric cancer tissues by qPCR and in situ hybridization (ISH), and its low expression was significantly correlated with postoperative metastasis and short overall survival time after surgery. Through the results of gain-of-function experiments, PART1 was confirmed as a tumor suppressor that can decrease not only cell viability, migration, and invasion in vitro but also tumorigenesis and tumor metastasis in vivo. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) showed that PART1 interacts with androgen receptor (AR), and then, promyelocytic leukemia zinc finger (PLZF) is upregulated in an androgen-independent manner. In a chain reaction, chromatin immunoprecipitation (ChIP) assay additionally illustrated that PLZF upregulation increased the enrichment of EZH2 and H3K27 trimethylation in the platelet-derived growth factor (PDGFB) promotor, thereby inhibition of PDGFB and the subsequent PDGFRβ/PI3K/Akt signaling pathway. Based on these findings, we showed PART1 plays a tumor suppressor role by promoting PLZF expression followed by recruitment of EZH2 to mediate epigenetic PDGFB silencing and downstream PI3K/Akt inhibition, suggesting that PART1 has a key role in restraining the aggressive ability of GC cells and providing a novel perspective on lncRNAs in GC progression.