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 in histones and diverse proteins, fostering tumor initiation and progression. Nonetheless, the impact of protein lactylation on the prognosis of non-specific triple-negative breast cancer (TNBC) remains uncertain. In the present study, the pan-lysine lactylation (panKlac) levels in cytoplasmic and nuclear compartments were semi-quantitatively examined using a tissue microarray encompassing 77 non-specific TNBC tissues. The association of the prognosis of patients with the panKlac levels in the cytoplasmic and nuclear compartments or other tumor attributes was assessed using Kaplan-Meier and Cox regression analyses. Furthermore, the molecular pathways involved in the promotional effect of lactylation on cell proliferation were determined through a transcriptomic analysis. The results indicated that the 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. The panKlac levels were also markedly elevated in the TNBC cell line, MDA-MB-231. Additionally, glycolysis inhibition significantly reduced the global panKlac levels and concurrently diminished cell proliferation. According to the 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.