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Phosphorylation of USP27X by PIM2 promotes glycolysis and breast cancer progression via deubiquitylation of MYC

Oncogene (2024)Cite this article

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Abstract

Aberrant cell proliferation is a hallmark of cancer, including breast cancer. Here, we show that USP27X is required for cell proliferation and tumorigenesis in breast cancer. We identify a PIM2-USP27X regulator of MYC signaling axis whose activity is an important contributor to the tumor biology of breast cancer. PIM2 phosphorylates USP27X, and promotes its deubiquitylation activity for MYC, which promotes its protein stability and leads to increase HK2-mediated aerobic glycolysis in breast cancer. Moreover, the PIM2-USP27X-MYC axis is also validated in PIM2-knockout mice. Taken together, these findings show a PIM2-USP27X-MYC signaling axis as a new potential target for breast cancer treatment.

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Fig. 1: USP27X is crucial for breast tumorigenesis.
Fig. 2: PIM2 phosphorylates USP27X at S71.
Fig. 3: USP27X S71 phosphorylation enhances MYC protein stability.
Fig. 4: USP27X S71 phosphorylation reduces the MYC ubiquitination.
Fig. 5: USP27X S71 phosphorylation promotes breast cancer cell glycolysis via MYC induced HK2 expression.
Fig. 6: USP27X S71 phosphorylation contributes to breast tumor growth.
Fig. 7: The protein expressions of PIM2, pS71-USP27X, and MYC positively correlate with each other in human breast cancer tissues.

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Data availability

The data and code underlying the findings of this study are available from the corresponding author on reasonable request. Raw sequencing data generated in this study was deposited at the Gene Expression Omnibus (GEO) under accession number GSE218202.

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Funding

The study was supported by research grants from the National Natural Science Foundation of China (Grant nos. 81972489 and 82003201), the National Natural Science Foundation of Shandong Province (Grant nos. ZR2020YQ58 and ZR2020QH255), Shandong Province College Science and Technology Plan Project (Grant no. J17KA254).

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  1. These authors contributed equally: Xue Han, Chune Ren, Chao Lu, Aifang Jiang.

Authors and Affiliations

  1. Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, PR China

    Xue Han, Chune Ren, Chao Lu, Aifang Jiang, Xiaoyun Wang, Lan Liu & Zhenhai Yu

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Contributions

XH, CER, CL, and AFJ performed experiments and analyzed data. XYW and LL provided access to material and facilities and contributed reagents. ZHY designed, supervised the project, and wrote the manuscript.

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Correspondence to Zhenhai Yu.

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All animal protocols were performed according to the guidelines and approved by the Institutional Animal Care and Use Committee of Weifang Medical University (Approval number: 2023SDL093). An informed consent form was signed by all patients in accordance with the Declaration of Helsinki, and the study was approved by the Affiliated Hospital of Weifang Medical University (Approval number: wyfy-2023-ky-030).

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Han, X., Ren, C., Lu, C. et al. Phosphorylation of USP27X by PIM2 promotes glycolysis and breast cancer progression via deubiquitylation of MYC. Oncogene (2024). https://doi.org/10.1038/s41388-024-03097-y

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