LUCAT1 Mediates MYC‐Targeted Suppression of Squamous Cell Carcinoma

Small‐molecule MYC inhibitors that directly target MYC are considered attractive cancer therapeutics. Here, we demonstrate that LUCAT1, a long noncoding RNA, serves as a critical mediator of MYC‐driven signaling in head and neck squamous cell carcinoma (HNSCC). The LUCAT1 expression is significantly downregulated in HNSCC cells following treatment with the MYC inhibitor MYCi975. Mechanically, MYC transcriptionally activates LUCAT1 through direct promoter binding, facilitating oncogenic functions. Clinically, elevated LUCAT1 is linked to cervical lymph node involvement in HNSCC and is associated with unfavorable patient outcomes. Functional studies in vitro demonstrated that LUCAT1 knockdown inhibits proliferation, migratory capacity, and invasive activity of HNSCC cells. This suppression also extends to the in vivo growth of tumors. Importantly, LUCAT1 overexpression attenuates the MYCi975 anti‐tumor effects on HNSCC, confirming its role in therapeutic resistance. These results establish LUCAT1 as both a biomarker of aggressive disease and a mediator of MYC‐driven oncogenesis, proposing LUCAT1 as a candidate synergistic therapeutic target in the treatment of HNSCC with MYC inhibition.