Abstract
The protein arginine methyltransferase 5 (PRMT5), which is highly expressed in tumour tissues, plays a crucial role in cancer development. However, the mechanism by which PRMT5 promotes cancer growth is poorly understood. Here, we report that PRMT5 contributes to lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours. Mass spectrometric analysis identified PRMT5 lysine 387 as its succinylation site. Moreover, the desuccinylation of PRMT5 K387 enhances the methyltransferase activity of PRMT5. SIRT7 catalyses the desuccinylation of PRMT5 in cells. The SIRT7-mediated dessuccinylation of PRMT5 lysine 387 fails to bind to STUB1, decreasing PRMT5 ubiquitination and increasing the interaction between PRMT5 and Mep50, which promotes the formation of the PRMT5-Mep50 octamer. The PRMT5-Mep50 octamer increases PRMT5 methyltransferase activity, leading to arginine methylation of SREBP1a. The symmetric dimethylation of SREBP1a increases the levels of cholesterol, fatty acid, and triglyceride biogenesis in the cells, escaping degradation through the ubiquitin-proteasome pathway. Functionally, the desuccinylation of PRMT5 K387 promotes lipid metabolism reprogramming, tumour growth and metastasis in vitro and in vivo in tumours.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 31670769), National Natural Science Foundation of China (No. 81970519), National Natural Science Foundation of China (No. 82173317), Programme for JLU Science and Technology Innovative Research Team (2017TD-08), Fundamental Research Funds for the Central Universities, TianQing Liver Disease Research Fund Subject (No. TQGB20200118), and National Science and Technology Major Project of China (No. 2018ZX10732101).
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HFY designed, performed experiments, analysed data, and wrote the manuscript. MZ designed, performed experiments, and analysed data. LNZ and HLY performed experiments and analysed data. GY, YY, YG, YFW and WZ performed experiments. JQN and TQS designed, oversaw experiments, technical and material support, and obtained funding. XDZ designed, oversaw experiments, interpreted data, technical and material support, obtained funding and wrote the manuscript.
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Yuan, Hf., Zhao, M., Zhao, Ln. et al. PRMT5 confers lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours. Acta Pharmacol Sin 43, 2373–2385 (2022). https://doi.org/10.1038/s41401-021-00841-y
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DOI: https://doi.org/10.1038/s41401-021-00841-y
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