Abstract 85: Puf60 drives tumor progression and therapy resistance in head and neck squamous cell carcinoma

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is a malignancy with high morbidity and mortality due to its invasive nature and frequent resistance to therapy. PUF60, a multifunctional RNA-binding protein, plays roles in transcription regulation and DNA repair, but its specific contributions to HNSCC pathogenesis remain unclear. This study investigates the role of PUF60 in tumor progression, oxidative stress responses, and resistance to therapeutic interventions. Methods: HNSCC cell lines were employed to study the functional effects of PUF60 overexpression and knockdown. Cellular assays assessed invasion, migration, and apoptosis under standard conditions and in response to oxidative stress, cisplatin, and radiation. DNA damage was analyzed using flow cytometry and Western blotting, while immunoprecipitation and subcellular fractionation were performed to explore interactions between PUF60 and vital regulatory proteins such as PTEN and Sirt6. Results: Overexpression of PUF60 significantly enhanced the invasive and migratory capabilities of HNSCC cells, while knockdown reduced these phenotypes. PUF60-overexpressing cells demonstrated resistance to cisplatin-induced apoptosis, accompanied by altered ROS production and decreased markers of DNA damage under oxidative stress. Radiation studies revealed a protective effect of PUF60, with reduced DNA damage and enhanced survival. Mechanistically, PUF60 modulated the subcellular localization of PTEN and interacted with Sirt6, highlighting its role in maintaining tumor cell viability under stress conditions. Conclusion: PUF60 is a crucial driver of HNSCC progression and therapy resistance, promoting tumor cell invasiveness, modulating responses to oxidative and genotoxic stress, and facilitating survival under therapeutic pressure. Targeting PUF60 may offer a novel approach to overcoming resistance and improving treatment outcomes in HNSCC. Citation Format: Jung Je Park, Chae Dong Yim, Ji Hyun Seo, So Young Cheon. Puf60 drives tumor progression and therapy resistance in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 85.