Inflammatory Cells Can Alter the Levels of H3K9ac and gamma H2AX in Dysplastic Cells and Favor Tumor Phenotype

Author(s)

Barbeiro, Camila de Oliveira ; Fernandes, Darcy ; Palacon, Mariana Paravani ; Castilho, Rogerio Moraes ; de Almeida, Luciana Yamamoto ; Bufalino, Andreia

• Document type: Journal article
• Source: JOURNAL OF PERSONALIZED MEDICINE; v. 13, n. 4, p. 15-pg., 2023-04-01.

Abstract

Oral potentially malignant disorders (OPMD) are clinical presentations that carry an increased risk of cancer development. Currently, epithelial dysplasia grade is based on architectural and cytological epithelial changes and is used to predict the malignant transformation of these lesions. However, predicting which OPMD will progress to a malignant tumor is very challenging. Inflammatory infiltrates can favor cancer development, and recent studies suggest that this association with OPMD lesions may be related to the etiology and/or aggressive clinical behavior of these lesions. Epigenetic changes such as histone modifications may mediate chronic inflammation and also favor tumor cells in immune resistance and evasion. This study aimed to evaluate the relationship between histone acetylation (H3K9ac) and DNA damage in the context of dysplastic lesions with prominent chronic inflammation. Immunofluorescence of "low-risk" and "high-risk" OPMD lesions (n = 24) and inflammatory fibrous hyperplasia (n = 10) as the control group was performed to assess histone acetylation levels and DNA damage through the phosphorylation of H2AX (gamma H2AX). Cell co-culture assays with PBMCs and oral keratinocyte cell lines (NOK-SI, DOK, and SCC-25) were performed to assess proliferation, adhesion, migration, and epithelial-mesenchymal transition (EMT). Oral dysplastic lesions showed a hypoacetylation of H3K9 and low levels of gamma H2AX compared to control. The contact of dysplastic oral keratinocytes with PBMCs favored EMT and the loss of cell-cell adhesion. On the other hand, p27 levels increased and cyclin E decreased in DOK, indicating cell cycle arrest. We conclude that the presence of chronic inflammation associated to dysplastic lesions is capable of promoting epigenetic alterations, which in turn can favor the process of malignant transformation. (AU)

• FAPESP's process: 18/04954-2 - Evaluation of the acetylation status of H3 histone and its contribution to genomic instability in oral leukoplakia and Proliferative Verrucous Leukoplakia
• Grantee: Camila de Oliveira Barbeiro
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 22/14672-0 - Study of the immune evasion mechanism in proliferative Verrucous Leukoplakia
• Grantee: Andreia Bufalino
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/22236-0 - Comparative analysis of lymphocytic infiltrate in oral leucoplastic lesions and oral lichen planus
• Grantee: Mariana Paravani Palaçon
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/01798-7 - In vitro study of the modulation of innate and adaptive immunity by dysplastic keratinocytes
• Grantee: Darcy Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/01438-0 - The role of the innate and adaptive immune responses in oral leukoplakia and oral proliferative verrucous leukoplakia
• Grantee: Andreia Bufalino
• Support Opportunities: Regular Research Grants