SART3 activates CD36 transcription by recruiting FOXM1 and activates PARP to augment cisplatin resistance in non-small cell lung cancer.

BACKGROUND

Cisplatin resistance remains a major barrier to effective lung cancer treatment. This study explores the function of spliceosome associated factor 3 (SART3) in cisplatin resistance in non-small cell lung cancer (NSCLC).

METHODS

H1299 and Calu-3 cells were exposed to incremental doses of cisplatin to generate resistant cell lines. SART3 deletion and re-expression was induced in these resistant cell lines, followed by analysis of cell viability, proliferation, and DNA damage and repair markers. Metabolic analysis was performed in cells upon SART3 loss or re-expression. Palmitic acid (PA) and Etomoxir, a CPT1A inhibitor, and gain- and loss-of-function assays of CD36 were applied to analyze the involvement of β-oxidation pathway in SART3-mediated cisplatin resistance. The interacting proteins of SART3 were explored using immunoprecipitation/liquid chromatography-mass spectrometry assays, and their effects on CD36 transcription were analyzed with immunoprecipitation and luciferase assays.

RESULTS

SART3 was upregulated in cisplatin-resistant NSCLC cells. SART3 deletion sensitized cells to cisplatin, whereas re-expression restored resistance. Mechanistically, SART3 enhanced DNA repair mainly through the PARP pathway, and its deletion increased gH2AX levels and reduced BrdU incorporation. Metabolic analysis revealed that SART3-driven resistance relied on elevated fatty acid (FA) β-oxidation. Targeting FA metabolism with CPT1A inhibitors or CD36 antagonists, or blocking PARP activity, significantly reversed SART3-mediated resistance. Further, SART3 recruited FOXM1 to activate CD36 transcription by modulating H2b deubiquitination. In vivo, inhibition of the SART3-CD36-PARP axis suppressed tumor growth and restored cisplatin sensitivity in mice.

CONCLUSION

This study suggests that SART3-driven metabolic reprogramming and DNA repair underpin cisplatin resistance.