CBX7 reprograms metabolic flux to protect against meningioma progression by modulating the USP44/c-MYC/LDHA axis

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外文摘要：Meningioma is one of the most common primary neoplasms in the central nervous system,whereas there is still no specific molec-ularly targeted therapy that has been approved for the clinical treatment of aggressive meningiomas.There is therefore an urgent demand to decrypt the biological and molecular landscape of malignant meningioma.Here,through the in-silica prescreening and 10-year follow-up of 445 meningioma patients,we uncovered that CBX7 is progressively decreased with malignancy grade and neoplasia stage in meningioma and a high CBX7 expression level predicts a favorable prognosis in meningioma patients.CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation.iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation.The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC proteins by transcriptionally inhibiting the expression of a c-MYC deubiquitinase,USP44,which attenuates c-MYC-mediated transactivation of LDHA transcripts and further inhibits glycolysis and subsequent cellular proliferation.More importantly,the functional role of CBX7 was further confirmed in both subcutaneous and orthotopic meningioma xenografts mouse models and human meningioma patients.Together,our results shed light on the critical role of CBX7 during meningioma malignancy progression and identified the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.

外文关键词：

CBX7meningiomaglycolysisUSP44c-MYCLDHAmalignancyglucose metabolism

作者：

Haixia Cheng、Lingyang Hua、Hailiang Tang、Zhongyuan Bao、Xiupeng Xu、Hongguang Zhu、Shuyang Wang、Zeyidan Jiapaer、Roma Bhatia、Ian F.Dunn、Jiaojiao Deng、Da?un Wang、Shuchen Sun、Shihai Luan、Jing Ji、Qing Xie、Xinyu Yang、Ji Lei、Guoping Li、Xianli Wang、Ye Gong

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作者单位：

Department of Pathology,Basic Medical School,Shanghai Medical College,Fudan University,Shanghai 200032,China

Department of Neurosurgery,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai,China

Department of Neurosurgery,The First Affiliated Hospital of Nanjing Medical University,Jiangsu,China

Xinjiang Key Laboratory of Biology Resources and Genetic Engineering,College of Life Science and Technology,Xinjiang University,Urumqi,China

Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA,USA

Department of Neurosurgery,University of Oklahoma Health Sciences Center,Oklahoma City,Oklahoma,USA

Fangshan Hospital of Beijing,University of Traditional Chinese Medicine,Beĳing,China

Center for Transplantation Science,Massachusetts General Hospital,Harvard Medical School,Boston,MA 02114,USA

Cardiovascular Research Center,Massachusetts General Hospital and Harvard Medical School,Boston,Massachusetts 02114,USA

School of Public Health,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Department of Critical Care Medicine,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

项目编号：

82072788817726748227159581900287

出版年：

2023

DOI：

10.1093/jmcb/mjad057

分子细胞生物学报(英文版)

中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD

影响因子：0.595

ISSN：1673-520X

年,卷(期)：2023.(10)

参考文献量54