YAP delactylation enhances therapy resistance in renal cell carcinoma

Rákkutatás · Renal cell carcinoma

By transfecting YAP‑K90T (a lactylation mimic), we enhanced antitumour immune activity.

Lactylation is a novel lysine acylation modification, and its function and exact mechanisms remain unclear. The responsiveness to combined targeted and immunotherapy continues to be a major challenge in cancer treatment. Here, we discovered that lysine lactylation (Kla) is specifically downregulated in targeted therapy‑resistant renal cancer cells and tissues. The lactylation status of YAP at lysine 90 (K90) regulates its nuclear translocation, which is critical for the expression of epithelial‑mesenchymal transition (EMT)-related genes and the PD‑L1 gene. Furthermore, we identified HDAC1 as the “eraser” of YAP‑K90 lactylation. By transfecting YAP‑K90T (a lactylation mimic), we enhanced antitumor immune activity. In xenograft models established in huCD34^+HSC NCG mice, we consistently found that HDAC1 inhibition enhances the response to combination therapy by increasing YAP lactylation and promoting CD8+ T cell tumor infiltration. These findings reveal lactylation as a key mechanism in targeted drug response and identify inhibiting YAP delactylation as a promising strategy for renal cell carcinoma treatment.

The study demonstrates that de‑lactylation of YAP by HDAC1 contributes to therapy resistance in renal cell carcinoma, and that re‑lactylating YAP restores immune‑mediated tumour control, identifying a novel therapeutic avenue.

Bizonyítékszint: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.

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