Epigenetic Modifications and Accumulation of DNA Double-Strand Breaks in Oral Lichen Planus Lesions Presenting Poor Response to Therapy

Abstract

Epigenetics refers to changes in cell characteristics that occur independently of modifications to the deoxyribonucleic acid (DNA) sequence. Alterations mediated by epigenetic mechanisms are important factors in cancer progression. Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive. We examined alterations in chromatin acetylation in oral lichen planus (OLP) with distinct clinical behavior and compared the alterations to the levels of DNA double-strand breaks (DSBs). We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci. Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy. Similar to H3K9ac, patients who responded poorly to therapy had increased accumulation of DNA DSB, indicating genomic instability. These findings suggest that histone modifications occur in OLP, and H3K9ac and γH2AX histones may serve as epigenetic markers for OLP recurrence.

Aberrant histone modification and inflammatory cytokine production of peripheral CD4+ T cells in patients with oral lichen planus

“…Previous studies have demonstrated aberrant histone modification is involved in autoimmune diseases and inflammatory disorders . In OLP research, a recent study provides evidence that acetylation modification of histone H3 at lys9 in lesion tissues is associated with poor response to therapy . Findings of these prior studies, in combination with the results of the current study, suggest that aberrant histone modification may play an important role in the pathogenesis of many autoimmune disorders, including OLP.…”

“…22,23 In OLP research, a recent study provides evidence that acetylation modification of histone H3 at lys9 in lesion tissues is associated with poor response to therapy. 24 Findings of these prior studies, in combination with the results of the current study, suggest that aberrant histone modification may play an important role in the pathogenesis of many autoimmune disorders, including OLP. Abnormal global H4 acetylation in CD4+ T was not observed in this study, suggesting that dysregulation of global histone acetylation may not be a general feature in CD4+ T cells.…”

Epigenetics of Aging and Alzheimer’s Disease: Implications for Pharmacogenomics and Drug Response

“…Patients with high levels of acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, failed to respond to therapy or experienced disease recurrence shortly after therapy. Similarly to H3K9ac, patients who responded poorly to therapy had increased accumulation of DNA DSB, indicating genomic instability [ 203 ]. Let-7 miRNA may be involved in the chemosensitivity of cancer cell lines in vitro .…”

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

“…Exploring the potential relevance of histone modifications to OPMD may provide early diagnostic indicators for OSCC and thus could reduce the associated incidence and mortality. Some findings implicated that histone modification aberrations were involved in early stages of OPMD malignant transformation and the onset of neoplasia (Chang et al, ; Dillenburg et al, ).…”

“…Accumulation of H3K9ac and DNA DSBs, as determined by higher γ‐H2A.X, was associated with poor response to therapy or increased flare rate in patients with OLP (Dillenburg et al, ).…”