Protein lactylation within the nucleus independently predicts the prognosis of non-specific triple-negative breast cancer

Protein lactylation represents a pervasive post-translational modification prevalent on histones and diverse proteins, fostering tumor initiation and progression. Nonetheless, it remains uncertain as to the impact of protein lactylation on the prognosis of non-specific triple-negative breast cancer (TNBC). Pan-lysine lactylation (panKlac) levels in cytoplasmic and nuclear compartments were semi-quantitatively examined with a tissue microarray encompassing 77 non-specific TNBC tissues. The association of panKlac levels in the cytoplasmic and nuclear compartments and other tumor attributes, with the prognosis of patients was assessed with Kaplan-Meier and Cox regression analyses. Furthermore, molecular pathways involved in the promotional effect of lactylation on cell proliferation were determined with a transcriptomic analysis. PanKlac levels were markedly higher in tumor tissues than in para-tumor mammary regions and showed no significant correlations with various clinicopathological parameters, such as tumor dimension, lymph node involvement, or histological grading. Notably, high panKlac levels within the nucleus served as an independent predictor of recurrence-free survival, whereas high cytoplasmic panKlac levels were a protective factor for patient survival. PanKlac levels were markedly elevated in the TNBC cell line MDA-MB-231. Additionally, glycolysis inhibition significantly reduced global panKlac levels and concurrently diminished cell proliferation. According to comprehensive transcriptomic analysis results, pathways related to ribosomal subunit biosynthesis/assembly and aminoacyl-tRNA biosynthesis were involved in the tumor-promoting mechanisms of lactylation. Further results revealed the oncogenic propensity of tyrosyl-tRNA synthetase 1 (YARS1) and its association with lactate production. Overall, Klac levels within the nucleus are an independent prognostic indicator for patients with non-specific TNBC. It is imperative to delve deeper into the roles and mechanisms of nuclear protein lactylation and YARS1 in non-specific TNBC.