N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis.
N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis.
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N6-甲基腺苷脱甲基酶 FTO 通过 SIVA1 介导的细胞凋亡增强结直肠癌的化疗耐药性
DOI：
10.1016/j.ymthe.2022.10.012
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发表时间：
2023-02-01
影响因子：
12.4
通讯作者：
He, Weiling
中科院分区：
文献类型：
--
作者：
Lin, Ziyou;Wan, Arabella H.;Sun, Lei;Liang, Heng;Niu, Yi;Deng, Yuan;Yan, Shijia;Wang, Qiao-Ping;Bu, Xianzhang;Zhang, Xiaolei;Hu, Kunhua;Wan, Guohui;He, Weiling
N6-甲基腺苷（m6 A）是最普遍的RNA修饰，被认为是RNA代谢中一种新的表观遗传调控。虽然m6 A修饰涉及多种生理过程，但其在结直肠癌（CRC）耐药中的作用仍然未知。我们使用MRM质谱法分析了人5-氟尿嘧啶（5-FU）耐药CRC组织中m6 A/A（%）的RNA表达谱，并使用m6 A RNA免疫沉淀试验来验证m6 A调节的靶点。我们的研究结果表明，m6 A脱甲基酶FTO在人类原发性和5-FU耐药CRC中上调。在体外和体内，FTO的消耗降低了5-FU耐药CRC细胞的细胞生长、集落形成和转移。从机制上讲，我们确定了SIVA 1，一个关键的凋亡基因，作为FTO介导的m6 A去甲基化的关键下游靶点。SIVA 1在CDS区域的m6 A去甲基化通过YTHDF 2依赖性机制诱导其mRNA降解。SIVA 1水平与临床结直肠癌组织中FTO水平呈负相关。值得注意的是，FTO的抑制通过FTO-SIVA 1轴显著降低了5-FU耐药CRC细胞中5-FU的耐受性，而SIVA 1消耗可以恢复CRC细胞中m6 A依赖性5-FU敏感性。总之，我们的研究结果证明了FTO作为m6 A脱甲基酶在CRC细胞中增强化学抗性的关键作用，并表明FTO抑制可以恢复化学抗性CRC细胞对5-FU的敏感性。Lin等人在5-FU耐药的结直肠癌细胞中，通过以YTHDF 2依赖性方式使SIVA 1 mRNA在编码区去甲基化，确定了FTO的上调。FTO抑制与5-FU联合使用可以恢复化疗耐药结直肠癌细胞对5-FU的敏感性。
N6-methyladenosine (m6A) is the most pervasive RNA modification and is recognized as a novel epigenetic regulation in RNA metabolism. Although the m6A modification involves various physiological processes, its roles in drug resistance in colorectal cancer (CRC) still remain unknown. We analyzed the RNA expression profile of m6A/A (%) with MRM mass spectrometry in human 5-fluorouracil (5-FU)-resistant CRC tissues, and used the m6A RNA immunoprecipitation assay to validate the m6A-regulated target. Our results have shown that the m6A demethylase FTO was up-regulated in human primary and 5-FU-resistant CRC. Depletion of FTO decreased cell growth, colony formation and metastasis in 5-FU-resistant CRC cells in vitro and in vivo. Mechanistically, we identified SIVA1, a critical apoptotic gene, as a key downstream target of the FTO-mediated m6A demethylation. The m6A demethylation of SIVA1 at the CDS region induced its mRNA degradation via a YTHDF2-dependent mechanism. The SIVA1 levels were negatively correlated with the FTO levels in clinical CRC tissues. Notably, inhibition of FTO significantly reduced the tolerance of 5-FU in 5-FU-resistant CRC cells via the FTO-SIVA1 axis, whereas SIVA1-depletion could restore the m6A-dependent 5-FU sensitivity in CRC cells. In summary, our findings demonstrate a critical role of FTO as an m6A demethylase enhancing chemo-resistance in CRC cells, and suggest that FTO inhibition may restore the sensitivity of chemo-resistant CRC cells to 5-FU. Lin et al. identified up-regulation of FTO in 5-FU-resistant colorectal cancer cells via demethylating SIVA1 mRNA at the coding region in a YTHDF2-dependent manner. Combination of FTO inhibition with 5-FU may restore the sensitivity of chemo-resistant colorectal cancer cells to 5-FU.
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N6-甲基腺苷修饰：抗癌药物开发的新药理学靶点
DOI：
10.1016/j.apsb.2018.06.001
发表时间：
2018-10
期刊：
Acta pharmaceutica Sinica. B
影响因子：
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作者：
Niu Y;Wan A;Lin Z;Lu X;Wan G
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影响因子：
50.3
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Huang, Yue;Su, Rui;Yang, Cai-Guang
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Yang, Cai-Guang
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影响因子：
28.5
作者：
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通讯作者：
Wang YZ
影响因子：
28.5
作者：
Jin, Dan;Guo, Jiwei;Su, Guoming
通讯作者：
Su, Guoming