Diferenças sexuais na acetilação de histonas e no desenvolvimento do carcinoma de células escamosas oral em modelo murino induzido por 4nqo e etanol

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-induced OSCC mouse model. Methods: 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 5mg/ml propylene glycol (PPG) or 100µg/mL 4NQO in drinking water, followed by either sterilized water or 8% ethanol (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 a decrease in OSCC. H3K9ac and H3K14 ac expression in males were lower in the 4NQO/EtOH group. H3K27ac was higher in dysplastic lesions compared to OSCC, particularly in females. Comparatively, females had a 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 demonstrate that the acetylation of H3K9, H3K14, and H3K27, along with the expression of KAT2A, plays a significant role in oral carcinogenesis, with notable sex specific differences. Female mice treated with 4NQO and EtOH exhibited increased histone acetylation and reduced KAT2A expression, which correlated with a lower incidence of OSCC. These findings underscore the importance of epigenetic modifications and sex-related factors in OSCC progression.