Journal of Molecular Cell Biology

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

Haixia Cheng^1,† , Lingyang Hua^2,† , Hailiang Tang^2,† , Zhongyuan Bao^3,† , Xiupeng Xu^3,† , Hongguang Zhu¹ , Shuyang Wang¹ , Zeyidan Jiapaer⁴ , Roma Bhatia⁵ , Ian F. Dunn⁶ , Jiaojiao Deng² , Daĳun Wang² , Shuchen Sun² , Shihai Luan² , Jing Ji³ , Qing Xie² , Xinyu Yang⁷ , Ji Lei^8,13 , Guoping Li^9,13 , Xianli Wang^10,* , Ye Gong^2,11,*

¹Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
²Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
³Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
⁴Xinjiang Key Laboratory of Biology Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China
⁵Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
⁶Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
⁷Fangshan Hospital of Beĳing, University of Traditional Chinese Medicine, Beĳing 102400, China
⁸Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
⁹Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
¹⁰School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
¹¹Department of Critical Care Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China
^†These authors contributed equally to this work
¹³Joint senior authors
^*Correspondence to:Xianli Wang , Email:wangxianli@shsmu.edu.cn Ye Gong , Email:gong_ye@fudan.edu.cn

J Mol Cell Biol, Volume 15, Issue 10, October 2023, mjad057, https://doi.org/10.1093/jmcb/mjad057

Keyword: CBX7, meningioma, glycolysis, USP44, c-MYC, LDHA, malignancy, glucose metabolism

Meningioma is one of the most common primary neoplasms in the central nervous system, but no specific molecularly targeted therapy has been approved for the clinical treatment of aggressive meningiomas. There is hence an urgent demand to decrypt the biological and molecular landscape of malignant meningioma. Here, through the in-silica prescreening and 10-year follow-up studies of 445 meningioma patients, we uncovered that CBX7 expression progressively decreases 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 protein by transcriptionally inhibiting the expression of a c-MYC deubiquitinase, USP44, consequently attenuates c-MYC-mediated transactivation of LDHA transcripts, and further inhibits glycolysis and subsequent cell proliferation. More importantly, the functional role of CBX7 was further confirmed in subcutaneous and orthotopic meningioma xenograft mouse models and meningioma patients. Altogether, our results shed light on the critical role of CBX7 in meningioma malignancy progression and identify the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.

Volume 15, Issue 10
October 2023