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Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis

Abstract

Metastasis accounts for the major cause of cancer-related mortality. How disseminated tumor cells survive under suspension conditions and avoid anoikis is largely unknown. Here, using a metabolic enzyme-centered CRISPR-Cas9 genetic screen, we identified methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) as a novel suppressor of anoikis. MTHFD1 depletion obviously restrained the capacity of cellular antioxidant defense and inhibited tumor distant metastasis. Mechanistically, MTHFD1 was found to bind the protein arginine methyltransferase 5 (PRMT5) and then undergo symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 was strengthened, which increased the symmetric dimethylation of MTHFD1. The elevated methylation of MTHFD1 largely augmented its metabolic activity to generate NADPH, therefore leading to anoikis resistance and distant organ metastasis. Therapeutically, genetic depletion or pharmacological inhibition of PRMT5 declined tumor distant metastasis. And R173 symmetric dimethylation status was associated with metastasis and prognosis of ESCC patients. In conclusion, our study uncovered a novel regulatory role and therapeutic implications of PRMT5/MTHFD1 axis in facilitating anoikis resistance and cancer metastasis.

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Fig. 1: MTHFD1 enhances anoikis resistance and metastasis of ESCC cells.
Fig. 2: Symmetric dimethylation of MTHFD1 is increased under suspension conditions.
Fig. 3: SDMA modification by PRMT5 increases enzymatic activity of MTHFD1.
Fig. 4: R173 is the major SDMA modification site of MTHFD1.
Fig. 5: PRMT5 inhibition increases anoikis and prevents cancer metastasis.
Fig. 6: Clinical significance of the PRMT5/MTHFD1 axis in ESCC.

Data availability

All data generated or analyzed during this study are included in this article and the Supplementary Information files.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (82022052, 82073112 and 81930065), Natural Science Foundation of Guangdong Province (2019A1515010233), Science and Technology Program of Guangdong (2019B020227002), Guangdong Esophageal Cancer Institute Science and Technology Program (M202003), National Natural Science Foundation of China (81802452, 82002465), Bureau of Education of Guangzhou Municipality (202032801) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-036).

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QM, YXL, CW, ZXW, and HQJ designed this work. QM and CW performed most of the experiments with the help of JFL, YTT, KL, XJL, and YH. QM, YXL, and ZXW analyzed and interpreted the data. QM, CW, KY, and YXL wrote this paper with the help of JJL, YTT, HL, and YYX. ZLZ, BL, HQJ, RHX edited and revised this paper. All the authors read and approved the final paper.

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Correspondence to Rui-Hua Xu or Huai-Qiang Ju.

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Meng, Q., Lu, YX., Wei, C. et al. Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis. Oncogene 41, 3912–3924 (2022). https://doi.org/10.1038/s41388-022-02387-7

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