The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer.
The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer.
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N6-甲基腺苷 METTL3 通过介导乳腺癌中肿瘤抑制因子 LATS1 的 m6A 甲基化来调节肿瘤发生和糖酵解
DOI：
10.1186/s13046-022-02581-1
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发表时间：
2023-01-07
期刊：
影响因子：
--
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肿瘤相关因子的转录后修饰在乳腺癌的进展中起着关键作用。然而，其潜在机制尚不清楚。癌细胞中的M6A修饰是动态的和可逆的，并且已经发现通过各种机制影响肿瘤的发生和进展。本研究通过Hippo通路中m6A甲基化对乳腺癌细胞增殖和代谢的调控机制进行了探讨。利用MeRIP-seq、RNA-seq和代谢组学-seq的组合揭示了乳腺癌组织和细胞中m6A修饰的图谱。我们通过RNA pull-down实验、RIP-qPCR、MeRIP-qPCR和RNA稳定性分析来确定乳腺癌细胞中m6A调控中m6A蛋白与LATS1之间的关系。体外和体内实验证实了m6A蛋白在乳腺癌细胞中的表达和生物学功能。此外，我们研究了YAP/TAZ的磷酸化水平和定位，发现乳腺癌细胞中m6A调控LATS1会影响Hippo通路的活性。我们证明m6A通过Hippo通路因子LATS1调控乳腺癌细胞增殖和糖酵解代谢发挥重要作用。METTL3是m6A的写者，YTHDF2是LATS1 mRNA的读者蛋白，在乳腺癌的肿瘤发生和糖酵解中都起着积极的促进作用。METTL3在LATS1 mRNA中诱导高水平的m6A修饰。YTHDF2鉴定了LATS1 mRNA中的m6A位点，降低了其稳定性。敲除METTL3或YTHDF2蛋白表达增加LATS1 mRNA表达，通过激活Hippo通路中的YAP/TAZ抑制乳腺癌肿瘤发生。综上所述，我们发现METTL3-LATS1-YTHDF2通路通过激活Hippo通路中的YAP/TAZ在乳腺癌的进展中发挥重要作用。在线版本包含补充材料，可在10.1186/s13046-022-02581-1获得。
Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway. A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells. We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway. The online version contains supplementary material available at 10.1186/s13046-022-02581-1.
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影响因子：
3
作者：
Wen B;Mei Z;Zeng C;Liu S
通讯作者：
Liu S
影响因子：
7
作者：
Rong D;Dong Q;Qu H;Deng X;Gao F;Li Q;Sun P
通讯作者：
Sun P
miRNA-HERC4 通路通过灭活肿瘤抑制因子 LATS1 促进乳腺肿瘤发生
影响因子：
21.1
作者：
Xu, Youqin;Ji, Kaiyuan;Xu, Yang
通讯作者：
Xu, Yang
影响因子：
10.9
作者：
Chen X;Zhou X;Wang X
通讯作者：
Wang X
DOI：
10.1001/jama.2020.9246
发表时间：
2020-07-21
期刊：
JAMA
影响因子：
--
作者：
Shieh Y;Tice JA
通讯作者：
Tice JA