Abstract 5698: Opposing roles of HOXC6 isoforms in promoting head and neck squamous cell carcinoma

Abstract HOXC6, a member of the homeobox (HOX) family is a homeoprotein transcription factor regulating embryonic development, differentiation, and pathways like TGF-β/smad, PI3K/Akt, and Wnt. Although aberration in HOXC6 promotes onset and progression of several cancers, our previous study indicated an oncogenic role of HOXC6 in head and neck squamous cell carcinoma (HNSCC). Despite its role in HNSCC progression, the specific role of HOXC6 in HNSCC lies nascent. Emerging evidence suggests that alternative splicing events of HOXC6 generate distinct isoforms with diverse biological functions. While the HOXC6 transcript variant 1 encodes the primary isoform, variant 2 differs in the 5' UTR coding region and produces a shorter N-terminal isoform. In this study, we performed in-silico analysis alongside in vitro functional studies to delineate the roles of the primary and short isoforms in HNSCC progression. In-silico analysis revealed isoform-specific expression patterns across HNSCC and correlated with clinical outcomes. Our in vitro data demonstrated that the primary isoform enhances cell proliferation and migration by activating oncogenic pathways, while the shorter isoform counteracts these effects by inhibiting cell proliferation and suppressing metastatic potential. These findings highlight the impact of alternative splicing in modulating HNSCC function and reveal the opposing roles of its isoforms in HNSCC progression. This study underscores the importance of targeting isoform-specific mechanisms for developing biomarkers and therapeutic strategies in HNSCC. Citation Format: Ishita Gupta, Subhendu Roy Choudhury, Anirudh Saxena, Madeleine Ndahayo, Vera Mukhina, Andrey Loginov, Nadya Vorobyeva, Daria A. Gaykalova. Opposing roles of HOXC6 isoforms in promoting 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 5698.