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Competition between p53 and YY1 determines PHGDH expression and malignancy in bladder cancer

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Abstract

Purpose

Serine metabolism is frequently dysregulated in many types of cancers and the tumor suppressor p53 is recently emerging as a key regulator of serine metabolism. However, the detailed mechanism remains unknown. Here, we investigate the role and underlying mechanisms of how p53 regulates the serine synthesis pathway (SSP) in bladder cancer (BLCA).

Methods

Two BLCA cell lines RT-4 (WT p53) and RT-112 (p53 R248Q) were manipulated by applying CRISPR/Cas9 to examine metabolic differences under WT and mutant p53 status. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and non-targeted metabolomics analysis were adopted to identify metabolomes changes between WT and p53 mutant BLCA cells. Bioinformatics analysis using the cancer genome atlas and Gene Expression Omnibus datasets and immunohistochemistry (IHC) staining was used to investigate PHGDH expression. Loss-of-function of PHGDH and subcutaneous xenograft model was adopted to investigate the function of PHGDH in mice BLCA. Chromatin immunoprecipitation (Ch-IP) assay was performed to analyze the relationships between YY1, p53, SIRT1 and PHGDH expression.

Results

SSP is one of the most prominent dysregulated metabolic pathways by comparing the metabolomes changes between wild-type (WT) p53 and mutant p53 of BLCA cells. TP53 gene mutation shows a positive correlation with PHGDH expression in TCGA-BLCA database. PHGDH depletion disturbs the reactive oxygen species homeostasis and attenuates the xenograft growth in the mouse model. Further, we demonstrate WT p53 inhibits PHGDH expression by recruiting SIRT1 to the PHGDH promoter. Interestingly, the DNA binding motifs of YY1 and p53 in the PHGDH promoter are partially overlapped which causes competition between the two transcription factors. This competitive regulation of PHGDH is functionally linked to the xenograft growth in mice.

Conclusion

YY1 drives PHGDH expression in the context of mutant p53 and promotes bladder tumorigenesis, which preliminarily explains the relationship between high-frequency mutations of p53 and dysfunctional serine metabolism in bladder cancer.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank Feng Zhang for supplying lenti-CRISPR v2 plasmid from addgene and the useful suggestion for plasmid extraction and lentivirus packaging.

Funding

This study was supported by funds from the National Natural Science Foundation of China (No. 82172920), National Natural Science Foundation for Young Scholars of China (No. 81902566) and Shanghai Jiaotong University Medical-Engineering Cross Research Fund (No. YG2019QNA53).

Author information

Author notes

  1. Tiezhu Shi, Zhihao Yuan and Yanying He have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Precise Genome Engineering Centre, School of Life Sciences, Guangzhou University, 510006, Guangzhou, China

    Tiezhu Shi, Yanying He & Xiongjun Wang

  2. Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 200080, Shanghai, China

    Tiezhu Shi, Zhihao Yuan, Dongliang Zhang, Siteng Chen, Jialiang Shao & Xiang Wang

  3. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, 200080, Shanghai, China

    Linli Yao

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  1. Tiezhu Shi
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Contributions

Conception and design: J. Shao, L. Yao and X. Wang. Development of methodology: Z. Yuan, Yan. He and T. Shi. Acquisition of data: T. Shi and Z. Yuan. Analysis and interpretation of data: J. Shao, T. Shi, Z. Yuan, D. Zhang, X. Wang, and S. Chen. Writing, review, and/or revision of the manuscript: L. Yao, XJ. Wang and T. Shi. Administrative, technical, or material support: J. Shao, Z. Yuan, D. Zhang, and Y. He. Study supervision: X. Wang.

Corresponding authors

Correspondence to Linli Yao, Jialiang Shao or Xiang Wang.

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All procedures related to patients were carried out in accordance with International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS). The study was approved by the Research Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University. All the animal studies were approved by the Institutional Committee for Animal Care and Use of Laboratory Animals prepared by Shanghai Jiao Tong University.

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Shi, T., Yuan, Z., He, Y. et al. Competition between p53 and YY1 determines PHGDH expression and malignancy in bladder cancer. Cell Oncol. 46, 1457–1472 (2023). https://doi.org/10.1007/s13402-023-00823-8

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