NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance.

ABSTRACT: Alternative polyadenylation (APA) is critical for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3' untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3' UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation "writer" catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic

SUBMITTER: Lin J 

PROVIDER: S-EPMC12116747 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature