N-α-Acetyltransferase 40 promotes oral squamous cell carcinoma progression by enhancing FEN1 transcription and suppressing CD8 T cell antitumor immunity.

Oral squamous cell carcinoma (OSCC) is the eighth most common malignancy worldwide and the predominant type of head and neck cancer. N-α-acetyltransferase 40 (NAA40), a histone acetyltransferase specifically modifying histones H4 and H2A, has been implicated in oncogenic processes across multiple tumor types. However, its role in OSCC remains unexplored. This study aimed to investigate the functional significance of NAA40 in OSCC and delineate its underlying molecular mechanisms. Bioinformatics analyses were performed to evaluate NAA40 expression and its prognostic value in OSCC tissues. Quantitative real-time PCR, western blot, chromatin immunoprecipitation, CD8 T cell isolation, co-culture, flow cytometry, and humanized immune-reconstituted subcutaneous xenograft/syngeneic transplantation models were used to clarify its function, mechanism, and therapeutic efficacy. Results showed that NAA40 was upregulated in OSCC tissues, and this upregulation was associated with worse overall survival in patients. In vitro experiments revealed that NAA40 overexpression inhibited T cell activation and their cytotoxic capacity against OSCC cells by upregulating programmed death-ligand 1 (PD-L1) expression, whereas NAA40 knockdown yielded the opposite effect. In vivo studies further suggested that downregulation of NAA40 effectively inhibited tumor growth in immunocompetent mice. Mechanistically, NAA40 promotes histone H4 lysine acetylation enrichment at the lap endonuclease-1 (FEN1) promoter and its transcriptional activation through an indirect mechanism, which is mediated by its regulation of H4 N-terminal acetylation at the first serine residue. This cascade ultimately upregulates PD-L1 expression. Knockdown of FEN1 reversed the suppression of CD8 T cell activation and antitumor immunity caused by NAA40 overexpression. This study demonstrates NAA40 promotes OSCC progression via enhancing FEN1 transcription and suppressing CD8 T cell function, suggesting that NAA40 may serve as a novel prognostic marker and therapeutic target for OSCC.