2. Academic Validation
  3. Tumor suppressor BAP1 suppresses disulfidptosis through the regulation of SLC7A11 and NADPH levels

Tumor suppressor BAP1 suppresses disulfidptosis through the regulation of SLC7A11 and NADPH levels

  • Oncogenesis. 2024 Sep 12;13(1):31. doi: 10.1038/s41389-024-00535-0.
Jin Wang # 1 2 3,  Minglin Wang # 3,  Shaobo Wu 4,  Yanan Zhu 3,  Kexin Fan 3,  Yuhan Chen 3,  Zhengtao Xiao 3,  Jing Chen 5,  Kangsheng Tu 6,  Dongsheng Huang 7 8,  Yilei Zhang 9,  Qiuran Xu 10 11
Affiliations

Affiliations

  • 1 The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
  • 4 Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China.
  • 5 Department of Obstetrics, Xi'an New Chang'an Maternity Hospital, Xi'an, Shaanxi, China.
  • 6 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 7 The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China. dshuang@hmc.edu.cn.
  • 8 Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, China. dshuang@hmc.edu.cn.
  • 9 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. zhangyilei@xjtu.edu.cn.
  • 10 The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China. windway626@sina.com.
  • 11 Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, China. windway626@sina.com.
  • # Contributed equally.
PMID: 39266549 DOI: 10.1038/s41389-024-00535-0
Abstract

BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like Apoptosis or Ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote Apoptosis and Ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the Cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP+/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.

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