Expressão aumentada da H3K14ac, HDAC2 e HDAC6 como marcador epigenético de transformação maligna de quelite actínica para carcinoma de células escamosas de lábio

Abstract

Ultraviolet radiation (UVR) acts as the primary carcinogenic agent in the lower lip, triggering a cascade of genetic events and complex epigenetic modifications that culminate in malignant transformation. Among these modifications, histone acetylation and histone deacetylase (HDAC) activity emerge as critical regulators of gene expression and genomic stability. This study aimed to evaluate, through immunohistochemistry, the acetylation profile of histone H3 at lysine 14 (H3K14ac) and the expression of HDAC2 and HDAC6 enzymes in a biological and temporal series of lip carcinogenesis. The sample comprised 97 paraffin-embedded specimens, categorized into: Normal Mucosa (NM; n=15), Actinic Cheilitis (AC; n=43), and Lip Squamous Cell Carcinoma (LSCC; n=39). Quantitative and semi-quantitative analysis revealed that H3K14ac exhibits a distinct biphasic dynamic: a drastic reduction in acetylation levels was observed in AC (26.3%) compared to NM, followed by a significant increase in LSCC (48.8%; p < 0.001), suggesting specific chromatin reprogramming during neoplastic invasion. Simultaneously, HDAC2 (predominantly nuclear) and HDAC6 (cytoplasmic) enzymes demonstrated progressive, linear overexpression with increasing severity of epithelial dysplasia, reaching peak intensity in LSCC (68.9% and 82% intense scores, respectively; p < 0.001). ROC (Receiver Operating Characteristic) curve analysis confirmed the high diagnostic value of the markers, notably for HDAC6, which presented an Area Under the Curve (AUC) of 0.864, indicating excellent discriminatory capacity between pre-malignant and malignant tissues. These findings indicate that histone code dysregulation and exacerbated HDAC activity are early and persistent events in UVR-induced lip carcinogenesis, positioning these epigenetic mechanisms as potential progression biomarkers and promising therapeutic targets for the clinical management of lip neoplasms.