Abstract 1539: Lactate induced c-Myc lactylation drives prostate cancer progression by influencing gene transcription

Abstract Prostate cancer (PCa) is a leading cause of cancer-related morbidity and mortality, characterized by complex metabolic reprogramming that supports tumor growth and progression. Recently, lactate has emerged as a critical factor in PCa metabolism, produced via aerobic glycolysis and influenced by oncogene/tumor suppressor gene mutations, androgen signaling, and hypoxia. Glycolytic cancer cells and cancer-associated fibroblasts can secrete lactate, fostering "symbiotic" interactions with oxidative cancer cells through lactate shuttling. Lactate accumulation subsequently promoting the lactylation of proteins which is a novel post-translational modification involving proteins that is induced by lactate. The Warburg effect emphasizes the importance of lactylation in cancer biology, influencing gene transcription and supporting rapid tumor growth. Excessive lactate production and rapid lactate transport in cancer cells are mainly driven by the upregulation of c-Myc which is a master regulator of multiple biological programs. Its persistent activation results in abnormal expression of glycolytic enzymes and lactate transporters, contributing to PCa progression. While c-Myc undergoes various post-translational modifications, the potential for c-Myc lactylation and its role in PCa development remain unexplored. Preliminary studies indicate that sodium lactate exposure increases lysine lactylation in PCa cells. We also show that c-Myc oncogene is lactylated. The lactylation of c-Myc not only promotes tumor growth but also contributes to the metabolic flexibility of PCa, enabling them to thrive in hypoxic and nutrient-deprived environments. Understanding the molecular mechanisms underlying c-Myc lactylation provides new insights into PCa biology and opens potential avenues for therapeutic intervention targeting metabolic pathways. Citation Format: Mithu Howlader, Amos Olalekan Akinyemi, Md Rakibul Alam, Jianlin Wang, Lixiang Gu, Zhiguo Li. Lactate induced c-Myc lactylation drives prostate cancer progression by influencing gene transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1539.