Abstract Castration-resistant prostate cancer (CRPC) constitutes an advanced stage of prostate cancer (PCa) that emerges following conventional androgen deprivation therapy (ADT). Docetaxel (DTX), a standard chemotherapeutic agent, is integral to the therapeutic regimen for CRPC. However, the development of resistance to DTX has significantly impeded its clinical efficacy. Histone lactylation and elevated lactate production are emerging as critical factors in cancer biology, yet their roles in CRPC and DTX resistance remain poorly understood. This study investigated the relationship between histone lactylation, lactate production, and DTX resistance in CRPC. Clinical analysis revealed significantly increased pan-lactylated protein (Pan Kla) expression in CRPC tissues compared to PCa, accompanied by elevated lactate production and lactate dehydrogenase (LDH) activity. Higher Pan Kla expression was linked to poor prognosis in CRPC. DTX-resistant CRPC (CRPC-R) samples exhibited significantly elevated Pan Kla and histone lactylation modifications, especially at H3K18la and H4K12la sites. Inhibition of lactate production using 2-deoxyglucose (2-DG) and oxamate reduced DTX resistance, suppressed cell migration, induced G0/G1 phase arrest, and promoted autophagy. Moreover, CNN1 was identified as a potential downstream target of histone lactylation modifications in CRPC. Elevated CNN1 expression correlated with increased lactylation and DTX resistance, whereas its inhibition reversed the effects of lactate inhibition on cell cycle progression and autophagy. In vivo, CNN1 overexpression counteracted the tumor-suppressive effects of lactate inhibition, restoring tumor growth and autophagy levels. These findings suggested that histone lactylation and lactate metabolism, mediated by CNN1, play a crucial role in DTX resistance and tumor progression in CRPC, offering potential therapeutic targets for overcoming chemoresistance in CRPC.
Mao et al. (2026) studied this question.