N(6)-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming.
N(6)-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming.
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N6-甲基腺苷介导的 LDHA 诱导通过代谢重编程增强结直肠癌细胞的化疗耐药性
DOI：
10.7150/thno.73746
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Chen, Zhuojia
中科院分区：
文献类型：
--
作者：
Zhang, Kun;Zhang, Tao;Yang, Yuhan;Tu, Wenling;Huang, Hongbin;Wang, Yujun;Chen, Yuzhuo;Pan, Kejian;Chen, Zhuojia
背景：5-氟尿嘧啶（5-FU）化疗耐药是影响结直肠癌（CRC）患者治疗效率的主要障碍，但5-FU耐药的确切分子机制尚未完全阐明。方法：比较5-FU耐药CRC细胞与亲本细胞的代谢谱，包括ATP生成、葡萄糖消耗、乳酸生成和耗氧量（OCR）。随后，我们进行了一系列体外和体内实验，以研究5-FU耐药CRC细胞代谢重编程的机制。结果：我们发现，与亲代细胞相比，耐5-FU的结直肠癌细胞显示出ATP生成、葡萄糖消耗、乳酸生成和OCR水平的增加。此外，在5-FU耐药的CRC细胞中观察到mRNA n6 -甲基腺苷（m6A）和甲基转移酶样3 （METTL3）水平升高。抑制或敲低METTL3可抑制糖酵解，恢复5-FU耐药CRC细胞的化学敏感性。从机制上讲，METTL3增强LDHA的表达，LDHA催化丙酮酸转化为乳酸，从而引发糖酵解和5-FU抗性。METTL3可以通过稳定缺氧诱导因子（HIF-1α） mRNA来增加LDHA的转录，此外，METTL3还可以通过其CDS区的甲基化和YTH结构域家族蛋白1 （YTHDF1）的募集来触发LDHA mRNA的翻译。靶向抑制METTL3/LDHA轴可显著提高CRC细胞的体外和体内5-FU敏感性。结论：我们的研究表明，METTL3/LDHA轴诱导的糖代谢是克服CRC细胞5-FU耐药的潜在治疗靶点。
Background: Chemoresistance to 5-fluorouracil (5-FU) is a major barrier to influence the treatment efficiency of colorectal cancer (CRC) patients, while the precise molecular mechanisms underlying 5-FU resistance remain to be fully elucidated. Methods: The metabolic profiles including ATP generation, glucose consumption, lactate generation, and oxygen consumption rate (OCR) in 5-FU resistant CRC cells were compared with those in their parental cells. Subsequently, a series of in vitro and in vivo experiments were carried out to investigate the mechanisms responsible for metabolic reprogramming of 5-FU resistant CRC cells. Results: We found that 5-FU resistant CRC cells showed increased levels of ATP generation, glucose consumption, lactate generation, and OCR as compared with those in their parental cells. Further, increased levels of mRNA N6-methyladenosine (m6A) and methyltransferase-like 3 (METTL3) were observed in 5-FU resistant CRC cells. Inhibition or knockdown of METTL3 can suppress glycolysis and restore chemosensitivity of 5-FU resistant CRC cells. Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1α), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells. Conclusion: Our study indicates that METTL3/LDHA axis-induced glucose metabolism is a potential therapy target to overcome 5-FU resistance in CRC cells.
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影响因子：
1.4
作者：
Alptekin A;Ye B;Ding HF
通讯作者：
Ding HF
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影响因子：
16
作者：
Qing Y;Dong L;Gao L;Li C;Li Y;Han L;Prince E;Tan B;Deng X;Wetzel C;Shen C;Gao M;Chen Z;Li W;Zhang B;Braas D;Ten Hoeve J;Sanchez GJ;Chen H;Chan LN;Chen CW;Ann D;Jiang L;Müschen M;Marcucci G;Plas DR;Li Z;Su R;Chen J
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Chen J
影响因子：
4
作者：
Shao X;Zheng X;Ma D;Liu Y;Liu G
通讯作者：
Liu G
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
影响因子：
11.2
作者：
Chen, Feng;Chen, Zhuojia;Wang, Hongsheng
通讯作者：
Wang, Hongsheng
m6A 依赖性糖酵解促进结直肠癌进展
影响因子：
37.3
作者：
Shen, Chaoqin;Xuan, Baoqin;Hong, Jie
通讯作者：
Hong, Jie