N6-Methyladenosine Regulates mRNA Stability and Translation Efficiency of KRT7 to Promote Breast Cancer Lung Metastasis
N6-Methyladenosine Regulates mRNA Stability and Translation Efficiency of KRT7 to Promote Breast Cancer Lung Metastasis
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N6-甲基腺苷调节KRT7 mRNA稳定性和翻译效率促进乳腺癌肺转移
DOI：
10.1158/0008-5472.can-20-3779
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Wang, Hongsheng
中科院分区：
文献类型：
--
作者：
Chen, Feng;Chen, Zhuojia;Wang, Hongsheng
RNA修饰在癌细胞器官转移过程中的作用尚不清楚。在此，我们通过三轮体内肺转移亚群筛选建立了乳腺癌肺转移细胞，并将其命名为BCLMF 3细胞。在这些细胞中，mRNA N-6-甲基腺苷（m（6）A）和甲基转移酶L3增加，而去甲基酶FTO减少。表观转录组和转录组分析以及功能研究确定角蛋白7（KRT 7）是m（6）A诱导的乳腺癌肺转移的关键效应子。具体而言，增加的胃L3在A877处甲基化KRT 7-AS以通过IGF 2BP 1/HuR复合物增加KRT 7-AS/KRT 7 mRNA双链体的稳定性。此外，YTHDF 1/eEF-1还参与了FTO调控的KRT 7 mRNA的翻译延长，其中KRT 7外显子6的A950甲基化是甲基化的关键位点。体内和临床研究证实了KRT 7、KRT 7-AS和胃L3在乳腺癌肺转移和临床进展中的重要作用。总体而言，m（6）A通过增加KRT 7-AS/KRT 7 mRNA双链体的稳定性和KRT 7的翻译促进乳腺癌肺转移。意义：本研究表明N-6-甲基腺苷是乳腺癌转移的关键驱动因子和潜在的治疗靶点。
The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BCLMF3 cells. In these cells, mRNA N-6-methyladenosine (m(6)A) and methyltransferaseMETTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m(6)A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation ofKRT7mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m(6)A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7.Significance: This study suggests that N-6-methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.