Department of Obstetrics and Gynecology, the Second Hospital of Dalian Medical University, Dalian, PR China.
Department of Pathology, the Second Hospital of Dalian Medical University, Dalian, PR China.
Biochim Biophys Acta Mol Cell Res. 2024 Dec;1871(8):119830. doi: 10.1016/j.bbamcr.2024.119830. Epub 2024 Aug 23.
High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect (P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6K. Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.
高级别浆液性卵巢癌（HGSOC）是最具侵袭性的卵巢癌类型，对女性健康构成极大威胁。因此，我们在临床样本中进行了 RNA 测序技术，以探索 HGSOC 进展的分子机制。我们注意到 BBOX1，一种 2-氧戊二酸依赖性酶，在 HGSOC 肿瘤组织中高度表达。功能研究表明，BBOX1 促进 HGSOC 细胞在体外和体内的存活和生长。野生型 BBOX1 的过表达促进了细胞增殖，但 Asn191 和 Asn292 突变（BBBOX1 酶活性的关键氨基酸）抵消了这种作用（P < 0.05），这表明 BBOX1 对 HGSOC 细胞增殖的促进作用与其催化活性有关。下调 BBOX1 降低了 mTORC1 途径的活性，降低了 IP3R3 的蛋白表达和 S6K 的磷酸化水平。代谢组学分析表明，BBOX1 参与了 HGSOC 细胞的葡萄糖代谢、氨基酸代谢和核苷酸代谢。此外，抑制 BBOX1 抑制了 HGSOC 细胞的糖酵解作用，降低了葡萄糖消耗、乳酸生成和糖酵解关键因子的表达。最后，我们发现缺氧诱导了 HGSOC 细胞中 BBOX1 的表达，并证实 BBOX1 可以被缺氧诱导因子-1α转录激活，其可以直接结合到 BBOX1 启动子上。综上所述，BBOX1 介导了由缺氧驱动的代谢重编程，并通过 mTORC1 途径影响细胞代谢，因此在 HGSOC 发展过程中作为癌基因发挥作用。
