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TMSB4Y restrains sphingomyelin synthesis via de novo purine synthesis to exert a tumor suppressor function in male esophageal squamous cell carcinoma

Oncogene volume 43, pages 3660–3672 (2024)Cite this article

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Abstract

Y chromosome genes play a vital role in sex difference of cancer. The dysregulation and functional implications of Y chromosome genes in esophageal squamous cell carcinoma (ESCC) remains elusive. Here, we analyze the Y chromosome gene signature and identify TMSB4Y as an emerging prognostic predictor in male ESCC. Functional analyses show that TMSB4Y inhibits the proliferation, invasion and metastasis of male ESCC cells. Mechanistically, we demonstrate that TMSB4Y interacts with PAICS, wherein TMSB4Y disrupts the formation of the PAICS octamer to inhibit purine de novo synthesis, leading to a decrease in the AMP/ATP ratio, subsequently impeding AMPK phosphorylation. Furthermore, we uncover a regulatory cascade orchestrated by the TMSB4Y/PAICS-AMPK axis, which exerts a suppressive effect on sphingomyelin metabolism by inhibiting the expression of sphingomyelin synthases (SMSs). Notably, Malabaricone C, an inhibitor of SMS1 and SMS2, effectively suppresses male ESCC cell proliferation and xenograft tumor growth. Collectively, these findings reveal the regulation of sphingomyelin metabolism by TMSB4Y/PAICS-AMPK axis and underscore the potential of targeting SMSs as a promising therapeutic approach for the treatment of male ESCC.

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Fig. 1: TMSB4Y is a potential tumor suppressor in male ESCC.
Fig. 2: TMSB4Y inhibits male ESCC proliferation.
Fig. 3: TMSB4Y exerts a tumor-suppressive function through its interaction with PAICS.
Fig. 4: TMSB4Y prevents the octamerization of PAICS to inhibit purine de novo synthesis.
Fig. 5: TMSB4Y-PAICS interaction decreases sphingomyelin via SMSs in male ESCC cells.
Fig. 6: SMSs are potential targets for male ESCC therapy.

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Data availability

The lipidomic data were upload to MetaboLight with accession number of MTBLS9834.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82188102, 82030089), National Key R&D Program of China (2020YFA0803303, 2022YFC3401003), CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2023-I2M-2-004, 2021-I2M-1-067), and the Fundamental Research Funds for the Central Universities (3332021091).

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Author notes

  1. These authors contributed equally: Tongyang Gong, Wanyuan Sun.

Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China

    Tongyang Gong, Wanyuan Sun, Jiahui Cai, Ning Zhao, Minyi Lu, Zhihua Liu & Hongyan Chen

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, PR China

    Tongyang Gong

  3. Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, PR China

    Xukun Li

  4. Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China

    Jiahui Cai

  5. Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, PR China

    Juan Xu

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Contributions

TG and WS contributed equally to this work. ZL and HC conceived the ideas and supervised the research. TG and WS performed the experiments. XL, JC, NZ, ML and JX performed some assistant works. TG, WS, HC and ZL discussed the results and wrote the manuscript. All authors have read and approved the article.

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Correspondence to Zhihua Liu or Hongyan Chen.

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Gong, T., Sun, W., Li, X. et al. TMSB4Y restrains sphingomyelin synthesis via de novo purine synthesis to exert a tumor suppressor function in male esophageal squamous cell carcinoma. Oncogene 43, 3660–3672 (2024). https://doi.org/10.1038/s41388-024-03193-z

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