脑膜瘤是中枢神经系统最常见的原发性肿瘤之一，但目前尚无特定的分子靶向疗法被批准用于临床治疗侵袭性脑膜瘤。因此，迫切需要解密恶性脑膜瘤的生物学和分子景观。在这里，通过对445名脑膜瘤患者进行硅胶预筛选和10年随访，我们发现CBX7随着脑膜瘤的恶性程度和肿瘤分期而逐渐降低，并且CBX7的高表达水平预示着脑膜瘤患者良好的预后。 CBX7 恢复显着诱导细胞周期停滞并抑制脑膜瘤细胞增殖。基于 iTRAQ 的蛋白质组学分析表明，CBX7 恢复触发了从糖酵解到氧化磷酸化的代谢转变。机制研究表明，CBX7 通过转录抑制 c-MYC 去泛素酶 USP44 的表达来促进 c-MYC 蛋白的蛋白酶体依赖性降解，USP44 减弱 c-MYC 介导的 LDHA 转录物反式激活，并进一步抑制糖酵解和随后的细胞增殖。更重要的是，CBX7的功能作用在皮下和原位脑膜瘤异种移植小鼠模型和人类脑膜瘤患者中得到了进一步证实。总之，我们的结果揭示了 CBX7 在脑膜瘤恶性肿瘤进展过程中的关键作用，并确定 CBX7/USP44/c-MYC/LDHA 轴是对抗脑膜瘤进展的有前景的治疗靶点。© 作者 2023。由牛津大学出版代表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出版社。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.