Arginine methylation of ALKBH5 by PRMT6 promotes breast tumorigenesis via LDHA-mediated glycolysis

Abstract

ALKBH5 is a master regulator of N6-methyladenosine (m⁶A) modification, which plays a crucial role in many biological processes. Here, we show that ALKBH5 is required for breast tumor growth. Interestingly, PRMT6 directly methylates ALKBH5 at R283, which subsequently promotes breast tumor growth. Furthermore, arginine methylation of ALKBH5 by PRMT6 increases LDHA RNA stability via m⁶A demethylation, leading to increased aerobic glycolysis. Moreover, PRMT6-mediated ALKBH5 arginine methylation is confirmed in PRMT6-knockout mice. Collectively, these findings identify a PRMT6-ALKBH5-LDHA signaling axis as a novel target for the treatment of breast cancer.

Keywords

PRMT6 / ALKBH5 / N6-methyladenosine / glycolysis / tumor growth

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Acknowledgements

The study was supported by research grants from National Natural Science Foundation of China (Nos. 81972489 and 82003201), National Natural Science Foundation of Shandong Province (Nos. ZR2020YQ58 and ZR2020QH255), Shandong Province College Science and Technology Plan Project (No. J17KA254), Projects of medical and health technology development program in Shandong Province (No. 2018WS057).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1028-4 and is accessible for authorized users.

Compliance with ethics guidelines

Conflict of interest Xue Han, Chune Ren, Aifang Jiang, Yonghong Sun, Jiayi Lu, Xi Ling, Chao Lu, and Zhenhai Yu declare that they have no conflict of interest.

All procedures performed in studies involving human samples were approved by the Ethics Committee of Weifang Medical University, and in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Patients gave written informed consent for participation, and the rest of the gene expression patient data sets are already published and publicly available. Animal experiments were performed according to the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals, and were approved by the ethics committee of Weifang Medical University.

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