MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma.
MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma.
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DOI：
10.1038/s41388-019-0869-4
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发表时间：
2019-08
期刊：
影响因子：
8
通讯作者：
Danesh FR
中科院分区：
文献类型：
--
作者：
Green NH;Galvan DL;Badal SS;Chang BH;LeBleu VS;Long J;Jonasch E;Danesh FR
一碳代谢在肿瘤细胞生存和生长所需的一系列代谢过程中起着核心作用。然而，单碳代谢如何影响RNA甲基化和肿瘤发生的分子基础在很大程度上仍不清楚。在这里，我们展示了MTHFD2，一种参与一碳代谢的线粒体酶，通过一种涉及HIF-2α的新的表位转录机制促进肾细胞癌的进展。我们发现MTHFD2在人肾细胞癌组织中的表达显著升高，并且MTHFD2基因的敲除显著降低了异种移植瘤的生长。机制上，使用无偏向甲基化RNA免疫沉淀测序方法，我们发现MTHFD2在控制全球N6-甲基腺苷(M6A)甲基化水平方面发挥关键作用，包括HIF-2α基因的M6A甲基化，从而导致HIF-2α的增强翻译。增强的HIF-2RNA翻译反过来促进有氧糖酵解，通过α甲基化将一碳代谢与HIF-2RNA依赖的代谢重编程联系起来。我们的发现还表明，MTHFD2和HIF-2α在肾癌中形成一个正前馈环，促进代谢重新编程和肿瘤生长。综上所述，我们的结果表明，在肾癌中，MTHFD2将RNA甲基化状态与肿瘤细胞的代谢状态联系起来。
One-carbon metabolism plays a central role in a broad array of metabolic processes required for the survival and growth of tumor cells. However, the molecular basis of how one-carbon metabolism may influence RNA methylation and tumorigenesis remains largely unknown. Here we show MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, contributes to the progression of renal cell carcinoma (RCC) via a novel epitranscriptomic mechanism that involves HIF-2α. We found that expression of MTHFD2 was significantly elevated in human RCC tissues, and MTHFD2 knockdown strongly reduced xenograft tumor growth. Mechanistically, using an unbiased methylated RNA immunoprecipitation sequencing (meRIP-Seq) approach, we found that MTHFD2 plays a critical role in controlling global N6-methyladenosine (m6A) methylation levels, including the m6A methylation of HIF-2α mRNA, which results in enhanced translation of HIF-2α. Enhanced HIF-2α translation, in turn, promotes the aerobic glycolysis, linking one-carbon metabolism to HIF-2α-dependent metabolic reprogramming through RNA methylation. Our findings also suggest that MTHFD2 and HIF-2α form a positive feedforward loop in RCC, promoting metabolic reprograming and tumor growth. Taken together, our results suggest that MTHFD2 links RNA methylation status to the metabolic state of tumor cells in RCC.
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影响因子：
29
作者：
Ducker GS;Chen L;Morscher RJ;Ghergurovich JM;Esposito M;Teng X;Kang Y;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
4.8
作者：
Long, Jianyin;Wang, Yin;Danesh, Farhad R.
通讯作者：
Danesh, Farhad R.
影响因子：
11.5
作者：
Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
DOI：
10.1007/978-1-4939-0805-9_4
发表时间：
2014-01-01
期刊：
TRANSCRIPTION FACTOR REGULATORY NETWORKS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Komata, Makiko;Katou, Yuki;Bando, Masashige
通讯作者：
Bando, Masashige
影响因子：
64.8
作者：
Cho H;Du X;Rizzi JP;Liberzon E;Chakraborty AA;Gao W;Carvo I;Signoretti S;Bruick RK;Josey JA;Wallace EM;Kaelin WG
通讯作者：
Kaelin WG