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  3. Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells

Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells

  • Cancer Res. 2025 Jul 25. doi: 10.1158/0008-5472.CAN-25-0419.
Guangqin Liu 1,  Haoqian Zhang 2,  Siqi Chen 1,  Jun Gao 2,  Haixin Zhao 3,  Yan Dong 1,  Changwei Liu 1,  Xuechen Wei 2,  Ting Li 2,  Chang Lu 2,  Haizhen Zhu 2,  Dingyi Lu 4,  Shiyu Feng 5,  Teng Li 3,  Weina Zhang 3,  Qing Xia 3,  Jianghong Man 3,  Tao Zhou 3,  Jiayi Chen 2,  Ailing Li 3,  Xin Pan 6
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China., Shanghai, China.
  • 2 Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, China., China.
  • 3 National Center of Biomedical Analysis, Beijing, China.
  • 4 National Center of Biomedical Analysis, China.
  • 5 Chinese PLA General Hospital, Beijing, China.
  • 6 National Center of Biomedical Analysis, Beijing, Beijing, China.
PMID: 40712058 DOI: 10.1158/0008-5472.CAN-25-0419
Abstract

Glioblastoma stem cells (GSCs) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. The mechanisms underlying this plasticity represent potential targetable vulnerabilities to improve glioblastoma treatment. Here, we identified a critical metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC survival and tumor initiation. MCU was preferentially expressed in GSCs, and loss of MCU significantly impaired GSC self-renewal and viability. Mechanistically, MCU enhanced mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation. Elevated acetyl-CoA levels drove histone H3K27 acetylation at the TRIB3 locus to maintain GSC growth. In glioblastoma patients, higher MCU expression was correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced TRIB3 expression, higher tumor grade, and poorer survival. Pharmacological inhibition of MCU with berberine suppressed GSC growth and extended survival in mouse GBM models. These findings establish MCU as a critical link between Mitochondrial Metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.

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