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Arginine and lysine methylation of MRPS23 promotes breast cancer metastasis through regulating OXPHOS

Oncogene volume 40, pages 3548–3563 (2021)Cite this article

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Abstract

Mitochondrial oxidative phosphorylation (OXPHOS) is a vital regulator of tumor metastasis. However, the mechanisms governing OXPHOS to facilitate tumor metastasis remain unclear. In this study, we discovered that arginine 21(R21) and lysine 108 (K108) of mitochondrial ribosomal protein S23 (MRPS23) was methylated by the protein arginine methyltransferase 7 (PRMT7) and SET-domain-containing protein 6 (SETD6), respectively. R21 methylation accelerated the poly-ubiquitin-dependent degradation of MRPS23 to a low level. The MRPS23 degradation inhibited OXPHOS with elevated mtROS level, which consequently increased breast cancer cell invasion and metastasis. In contrast, K108 methylation increased MRPS23 stability, and K108 methylation coordinated with R21 methylation to maintain a low level of MRPS23, which was in favor of supporting breast cancer cell survival through regulating OXPHOS. Consistently, R21 and K108 methylation was correlated with malignant breast carcinoma. Significantly, our findings unveil a unique mechanism of controlling OXPHOS by arginine and lysine methylation and point to the impact of the PRMT7-SETD6-MRPS23 axis during breast cancer metastasis.

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Fig. 1: MRPS23 is methylated at R21 by PRMT7.
Fig. 2: MRPS23 R21 methylation potentiates breast cancer cell metastasis through inhibiting OXPHOS.
Fig. 3: MRPS23 R21 methylation promotes the degradation of MRPS23 protein to a low level.
Fig. 4: MRPS23 K108 methylation coordinates with R21 methylation to maintain the low level of MRPS23.
Fig. 5: MRPS23 K108 methylation plays an essential role in breast cancer cell survival through regulating OXPHOS.
Fig. 6: MRPS23 R21 and K108 methylation is associated with a high grade of breast carcinoma.
Fig. 7: A proposed model for the arginine and lysine methylation of MRPS23 to regulate the stability of MRPS23 protein.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (grant numbers: 31770825, 31571317, 31570718, 31771335, and 31870765) and the Science and Technology Development Project of Jilin province (grant number: 20180101232JC, 20180101234JC, and 20200404106YY).

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Authors and Affiliations

  1. The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China

    Lingxia Liu, Xiliu Zhang, Xin Liu, Jiwei Liu, Cong Lin, Baiqu Huang & Jun Lu

  2. The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China

    Huayi Ding, Yingqi Liu, Na Zhang, Jingyao Hou & Yu Zhang

  3. Division of Clinical Research, First Hospital of Jilin University, Changchun, China

    Donghui Cao

  4. National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China

    Guannan Wang

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LL performed research, analyzed results, and wrote the paper. XZ, HD, GW, JH, and DC performed research. XL, NZ, JL, CL, and YL provided critical reagents. JL, YZ, and BH designed and performed research, analyzed results, and wrote the paper.

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Liu, L., Zhang, X., Ding, H. et al. Arginine and lysine methylation of MRPS23 promotes breast cancer metastasis through regulating OXPHOS. Oncogene 40, 3548–3563 (2021). https://doi.org/10.1038/s41388-021-01785-7

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