LNC942 promoting METTL14-mediated m6A methylation in breast cancer cell proliferation and progression
LNC942 promoting METTL14-mediated m6A methylation in breast cancer cell proliferation and progression
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LNC942 促进 METTL14 介导的 m(6)A 甲基化在乳腺癌细胞增殖和进展中的作用
DOI：
10.1038/s41388-020-1338-9
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发表时间：
2020-06-23
期刊：
影响因子：
8
通讯作者：
Wu, Huizhe
中科院分区：
文献类型：
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作者：
Sun, Tong;Wu, Zhikun;Wu, Huizhe
越来越多的证据支持，在N6-甲基腺嘌呤(m(6)A)的表观遗传修饰水平上，长非编码RNA(LncRNAs)在肿瘤的发生和发展中起着主要的调节作用。然而，乳腺癌(BRCA)的潜在调控机制仍然难以捉摸。在此，我们揭示了LINC00942(LNC942)在BRCA的发生和发展过程中作为癌基因发挥作用，促进METTL14介导的m(6)A甲基化，并调节其靶基因CXCR4和CYP1B1的表达和稳定性。具体地说，LNC942和METTL14在BRCA细胞和我们包括的BRCA队列(n=150)中伴随m(6)A水平的上调而显著上调。在功能上，LNC942在促进细胞增殖、集落形成和抑制细胞凋亡方面具有很强的致癌作用，从而提高了METTL14介导的m(6)A甲基化水平及其相关的CXCR4和CYP1B1的mRNA稳定性和蛋白表达。在机制上，LNC942通过携带特异性识别序列(+176-+265)直接招募METTL14蛋白，从而在体内外通过转录后m(6)A甲基化修饰稳定包括CXCR4和CYP1B1在内的LNC942下游靶基因的表达。因此，我们的结果揭示了一个新的LNC942-METTL14-CXCR4/CYP1B1信号轴，为BRCA的防治提供了新的靶点和串扰m(6)表观遗传修饰机制。
Increasing evidence supports that long noncoding RNAs (lncRNAs) act as master regulators involved in tumorigenesis and development at theN6-methyladenine (m(6)A) epigenetic modification level. However, the underlying regulatory mechanism in breast cancer (BRCA) remains elusive. Here, we unveil that LINC00942 (LNC942) exerts its functions as an oncogene in promoting METTL14-mediated m(6)A methylation and regulating the expression and stability of its target genes CXCR4 and CYP1B1 in BRCA initiation and progression. Specifically, LNC942 and METTL14 were significantly upregulated accompanied with the upregulation of m(6)A levels in BRCA cells and our included BRCA cohorts (n = 150). Functionally, LNC942 elicits potent oncogenic effects on promoting cell proliferation and colony formation and inhibiting cell apoptosis, subsequently elevating METTL14-mediated m(6)A methylation levels and its associated mRNA stability and protein expression of CXCR4 and CYP1B1 in BRCA cells. Mechanistically, LNC942 directly recruits METTL14 protein by harboring the specific recognize sequence (+176-+265), thereby stabilized the expression of downstream targets of LNC942 including CXCR4 and CYP1B1 through posttranscriptional m(6)A methylation modification in vitro and in vivo. Therefore, our results uncover a novel LNC942-METTL14-CXCR4/CYP1B1 signaling axis, which provides new targets and crosstalk m(6)A epigenetic modification mechanism for BRCA prevention and treatment.