Sex‐Related Differences in Histone Acetylation and Tumor Development in a 4‐Nitroquinoline 1‐Oxide and Ethanol‐Induced Oral Squamous Cell Carcinoma Mouse Model

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ABSTRACT Background Oral squamous cell carcinoma (OSCC) is one of the most frequent head and neck cancers. The 4‐nitroquinoline 1‐oxide (4NQO) mouse model of oral carcinogenesis is a well‐established model to investigate the mechanism behind OSCC development, including epigenetic alterations. Studies have shown that histone acetylation is a key regulator of gene expression and may play a role in such a tumor. This study investigates the acetylation of H3K9, H3K14, and H3K27 and the KAT2A gene expression in a sex‐based approach in a 4NQO/ethanol (EtOH)‐induced OSCC mouse model. Methods A total of 120 C57Bl/6J mice (60 males and 60 females) were divided into four groups ( n = 15). In the first 10 weeks, they were treated with 5 mg/mL propylene glycol (PPG) or 100 μg/mL 4NQO in drinking water, followed by either sterilized water or 8% EtOH for 15 weeks. After euthanasia, tongues were analyzed histopathologically. Immunohistochemistry and qPCR were also employed to study the histones and gene expression. Results Female mice showed increased H3K9ac and H3K14ac expression from normal mucosa to dysplasia, followed by decreased expression in OSCC. H3K9ac and H3K14ac expression in males was lower in the 4NQO/EtOH group. H3K27ac was higher in dysplastic lesions compared to OSCC, particularly in females. Comparatively, females had higher H3K9ac and H3K14ac expression in the 4NQO/EtOH group than males. KAT2A expression was lower in females treated with PPG/EtOH and 4NQO/H 2 O than in males. Conclusion Our results indicate that H3 acetylation and KAT2A gene expression may play a key role in oral carcinogenesis on a sex‐related basis.

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