BAP1 inactivation promotes lactate production by leveraging the subcellular localization of LDHA in melanoma.

Abstract

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.