High NSUN3 expression linked to poor survival in oral squamous cell carcinoma

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Frontiers in Medicine Published April 22, 2026 Medically reviewed April 25, 2026 DOI ↗ By Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

Key Takeaway

Note that high NSUN3 expression is an independent risk factor for poor survival in OSCC.

This cohort study included 60 patients with oral squamous cell carcinoma (OSCC). Analysis of tissue samples revealed that NSUN3 expression was significantly upregulated in OSCC tissues compared to normal or low expression levels. The study identified high NSUN3 expression as an independent risk factor for poor overall survival, although specific statistical measures such as p-values or confidence intervals were not reported.

In mechanistic experiments using SCC15 and SCC25 cell lines, knockdown of NSUN3 suppressed cell proliferation, migration, and invasion. Additionally, this intervention inhibited autophagy activity, evidenced by reduced LC3 puncta, decreased autophagosome number, lower Beclin1, a reduced LC3-II/I ratio, and increased P62/SQSTM1. These changes were associated with increased phosphorylation, leading to the inactivation of FOXO1 and FOXO3, which suppressed the FOXO signaling pathway.

Rapamycin treatment reversed the effects of NSUN3 knockdown and partially restored malignant phenotypes. The study notes that NSUN3 may promote OSCC progression through autophagy activation and FOXO pathway modulation. However, the study is based on a cohort of 60 patients, and mechanistic data were derived from cell lines. Adverse events, serious adverse events, discontinuations, and tolerability were not reported. The role of NSUN3 in OSCC remains largely unexplored, and autophagy plays a dual role in cancer.

Study Details

Study typeCohort

EvidenceLevel 3

PublishedApr 2026

View Original Abstract ↓

BackgroundOral squamous cell carcinoma (OSCC) is a prevalent malignancy with high rates of lymph node metastasis and recurrence, contributing to persistently poor clinical outcomes. RNA 5-methylcytosine (m5C) modification, mediated by methyltransferases such as NSUN3, is implicated in tumor progression; however, the specific function of NSUN3 in OSCC remains largely unexplored. Autophagy plays a dual role in cancer, and the FOXO pathway is a key regulator of autophagy. This study aimed to elucidate the function of NSUN3 in OSCC and its potential mechanism involving autophagy and FOXO signaling.MethodsNSUN3 expression profiles were characterized in OSCC tissues and cell lines using immunohistochemistry, qRT−PCR, and Western blot. Clinicopathological correlations and survival analyses were performed on a cohort of 60 OSCC patients. NSUN3 was knocked down in SCC15 and SCC25 cells using lentiviral shRNA. Cell proliferation, migration, and invasion were assessed by CCK-8, wound-healing, and Transwell assays. Autophagy activity was evaluated by immunofluorescence (LC3 puncta formation), electron microscopy (autophagosome quantification), and Western blot (LC3-II/I ratio, Beclin1, P62/SQSTM1). The autophagy agonist rapamycin was used to rescue phenotypic changes. The activity of the FOXO pathway was assessed by detecting phospho-FOXO1/FOXO3.ResultsNSUN3 was significantly upregulated in OSCC tissues and cells. Elevated NSUN3 expression, along with advanced pTNM stage and lymph node metastasis, constituted independent risk factors for poor overall survival. NSUN3 knockdown suppressed OSCC cell proliferation, migration, and invasion. Mechanistically, NSUN3 depletion inhibited autophagy, as evidenced by reduced LC3 puncta, decreased autophagosome number, lower Beclin1 expression, a reduced LC3-II/I ratio, and increased P62/SQSTM1 levels. Rapamycin treatment reversed these effects and partially restored malignant phenotypes. Furthermore, NSUN3 knockdown increased the phosphorylation (inactivation) of FOXO1 and FOXO3, thereby suppressing the FOXO signaling pathway.ConclusionNSUN3 is overexpressed in OSCC and is an independent prognostic factor. It promotes OSCC progression by enhancing autophagy, potentially through modulating the FOXO pathway. Targeting NSUN3 may represent a novel therapeutic strategy for OSCC.