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

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/H₂O 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.