Zheng Guopei, Shi Jiahao, Li Qian, Jin Xiaoliang, Fang Yan, Zhang Zhe, Cao Qin, Zhu Lili, Shen Jianfeng
Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Cell Death Discov. 2024 Nov 26;10(1):483. doi: 10.1038/s41420-024-02250-6.
BRCA1-associated protein 1 (BAP1) acts as a tumor suppressor and can affect the cell cycle, tumor immunity, and cellular metabolism through multiple pathways. In melanoma, BAP1 mutations promote tumor cell glycolysis, leading to increased lactate production. The tumor microenvironment with high lactate levels is often associated with immunosuppression and tumor progression. The inhibitory effect of BAP1 on glycolysis has been found in a variety of tumors, but the specific mechanism by which BAP1 inhibits lactate production still needs to be elucidated. In this study, we show that BAP1 can interact directly with lactate dehydrogenase (LDHA), causing LDHA to accumulate in the nucleus. Conversely, BAP1 deletion leads to the accumulation of LDHA in the cytoplasm, catalyzing the production of lactate from pyruvate that results in increased lactate levels inside and outside the cell. By elucidating the interaction between BAP1 and LDHA and the subsequent effects on lactate production in melanoma cells, this work provides insights into the mechanism of BAP1-mediated metabolic regulation. Furthermore, it may provide novel directions for the clinical treatment of BAP1-mutant melanoma.
乳腺癌1号关联蛋白1（BAP1）作为一种肿瘤抑制因子，可通过多种途径影响细胞周期、肿瘤免疫和细胞代谢。在黑色素瘤中，BAP1突变会促进肿瘤细胞的糖酵解，导致乳酸生成增加。高乳酸水平的肿瘤微环境通常与免疫抑制和肿瘤进展相关。在多种肿瘤中均发现了BAP1对糖酵解的抑制作用，但其抑制乳酸生成的具体机制仍有待阐明。在本研究中，我们发现BAP1可直接与乳酸脱氢酶A（LDHA）相互作用，导致LDHA在细胞核中积累。相反，BAP1缺失会导致LDHA在细胞质中积累，催化丙酮酸生成乳酸，从而导致细胞内外乳酸水平升高。通过阐明BAP1与LDHA之间的相互作用以及对黑色素瘤细胞乳酸生成的后续影响，本研究为BAP1介导的代谢调控机制提供了见解。此外，它可能为BAP1突变型黑色素瘤的临床治疗提供新的方向。
