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

Author:

Cheng Haixia1,Hua Lingyang2,Tang Hailiang2,Bao Zhongyuan3,Xu Xiupeng3,Zhu Hongguang1,Wang Shuyang1,Jiapaer Zeyidan4,Bhatia Roma5,Dunn Ian F6,Deng Jiaojiao2,Wang Daijun2,Sun Shuchen2,Luan Shihai2,Ji Jing3,Xie Qing2,Yang Xinyu7,Lei Ji8,Li Guoping9,Wang Xianli10,Gong Ye211

Affiliation:

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

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

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

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

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

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

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

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

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

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

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

Abstract

Abstract Meningioma is one of the most common primary neoplasms in the central nervous system, whereas there is still no specific molecularly 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.

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Genetics,Molecular Biology,General Medicine

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