Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma

Abstract

BACKGROUND: Patterns of global histone modifications have been suggested to be predictors of clinical outcome in many cancers. However, the role of global histone modification patterns in oral squamous cell carcinoma (OSCC) is unclear. METHODS: A retrospective clinicopathologic analysis was undertaken of 186 patients with oral squamous cell carcinoma who received complete ablative surgical treatment. Tissue arrays were made from those paraffin-embedded OSCC samples and examined by immunohistochemistry for histone 3 lysine 4 acetylation (H3K4ac), histone 3 lysine 18 acetylation (H3K18ac), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3). RESULTS: A low level of H3K4ac and a high level of H3K27me3 were associated with advanced T status, N status, tumor stage, and perineural invasion. They were also correlated with cancer-specific survival (CSS) and disease-free survival (DFS). The 5-year CSS and DFS in H3K4ac low vs. H3K4ac high were 74.8% versus 92.5% (P 5.010), and 51.4% versus 76.2% (P 5.001), respectively. The 5-year CSS and DFS in H3K27me3 low versus H3K27me3 high were 94.7% versus 62.3% (P <.001) and 76.4% versus 32.3% (P <.001), respectively. We also found improved prediction for DFS after combining the H3K4ac low and H3K27me3 high profiles and comparing the scores with the other modification patterns (P <.0001). CONCLUSIONS: This research demonstrates the potential prognostic utility of global histone modification analysis for OSCC. Cancer 2013;119:4259-67. V C 2013 American Cancer Society.KEYWORDS: histone modification, oral squamous cell carcinoma, prognosis. INTRODUCTIONOral squamous cell carcinoma (OSCC) is one of the most distressing diseases worldwide and is characterized by high localregional recurrence and poor long-term survival rates. The most decisive factors affecting the prognosis of patients with OSCC are the nodal status and the stage of the disease. Despite advancements made in the field of oral cancer early detection and multimodality treatment according to different clinicopathologic prognosticators, there has only been minor improvement in the response rate to current therapeutic strategies, particularly for tumors diagnosed in advanced stages. 1 There are likely substantial prognostic factors at the molecular level that contribute to the biological behavior of the tumors.Cancer is now considered a disease of genetic and epigenetic alterations. 2 Evidence has shown that the accumulation of a wide range of both genetic and epigenetic alterations in a multistep process promotes tumorigenesis and cancer progression. Genetic alterations are irreversible changes in a DNA sequence that can lead to either oncogene activation or tumorsuppressor gene inactivation. 3 In contrast, epigenetic changes are heritable and potentially reversible modifications in gene expression that occur without alterations to the DNA sequence. 4 In the past decade, epigenetic alterations, which include DNA methylation, the modifi...

Clinical implications of epigenetic regulation in oral cancer

“…Besides, methylation at H3K27 correlated with the clinico-pathological parameters i.e. size of tumor, nodal status, tumor stage and perineural invasion [99]. Further, Chromatin immunoprecipitation (ChIP) studies for H3K9me3 in keratinocyte cell line (OKF6-TERTIR) and tongue carcinoma cell line (SCC-9) corroborated differential expression in the normal and cancer cell lines.…”

“…Cumulative studies on histone modifications in oral cancers demonstrated methylation of H3 histone at specific lysine molecule positions-K4 in 39% (n = 145), K9 in 47% (n = 199) and K27 in 45% (n = 160) oral cancers. Acetylation of lysines on H3 histone was reported at positions K4 in 37% (n = 171), K9 in 80% (n = 10) and K18 in 39% (n = 152) of oral cancers [98][99][100]. Besides, methylation at H3K27 correlated with the clinico-pathological parameters i.e.…”

“…In oral cancers, lysine molecules on H3 histone at specific positions Lys4, Lys9, Lys18 and Lys27 are methylated and/or acetylated [98][99][100]. Cumulative studies on histone modifications in oral cancers demonstrated methylation of H3 histone at specific lysine molecule positions-K4 in 39% (n = 145), K9 in 47% (n = 199) and K27 in 45% (n = 160) oral cancers.…”

Epigenetic Regulation of Gene Expression in Head and Neck Squamous Cell Carcinoma: Therapeutic Perspectives

“…Избыточная активность деацетилаз (HDAC, histone deacetylase), катализирующих удаление ацетильной группы ε-N-ацетил-лизина, рассматрива-ется как один из ключевых факторов канцерогенеза [16]. Особенности профиля ацетилирования и триме-тилирования гистонов коррелируют с клиническими признаками агрессивности ОГШ (размер опухоли, вовлеченность лимфатических узлов, периневральная инвазия), что свидетельствует о значимой патогенети-ческой роли фактора посттрансляционной модифика-ции гистонов [17].…”

Epigenetic modifications in oral squamous cell carcinoma

“…7,8 Global histone modifications are known to be altered in tumor cells, and modification patterns can show correlation with clinical pathological factors, including oral squamous cell carcinoma. 9,10 In addition, a variety of global histone modifications have been studied in different types of cancer, many of which are used as prognosis predictors, especially the events of methylation and acetylation. 11 Studies assessing the enzymes responsible for promotion of histone modifications have been conducted in several types of cancer, such as SUV39H1, a histone methyltransferase wherein imunoexpression displayed correlation with the tumor stage of oral squamous cell carcinoma.…”