Menghan Zhou1,2, Yiping Li3, Shaofeng Lin4,5, Yanping Chen6, Yanyan Qian1, Zhujiang Zhao1, Hong Fan7. 1. Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China. 2. Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, 210018, China. 3. Department of Pathology, Medical School, Southeast University, Nanjing, 210009, China. 4. Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, 210009, China. 5. Department of Oncology, Fujian Provincial Cancer Hospital, Fuzhou, 350000, China. 6. Department of Pathology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China. 7. Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China. fanh@seu.edu.cn.
Abstract
BACKGROUND: Histone methylation, as an essential pattern of posttranslational modifications, contributes to multiple cancer-related biological processes. Dysregulation of histone methylation is now considered a biomarker for cancer prognosis. AIMS: This study investigated and evaluated the potential role of four histone lysine trimethylation markers as biomarkers for esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: Tissue arrays were made from 135 paraffin-embedded ESCC samples and examined for histone markers by immunohistochemistry, and 10 pairs of cancer and noncancerous mucosa tissues from ESCC patients were investigated with Western blot. Chi-squared test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard trend analyses were performed to assess the prognostic values of the markers. RESULTS: Histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 4 lysine 20 trimethylation (H4K20me3), but not histone 3 lysine 36 trimethylation (H3K36me3), showed stronger immunostaining signals in tumor tissues than in the corresponding adjacent non-neoplastic mucosa tissues. The expression patterns of H3K36me3, H3K9me3, and H4K20me3 correlated with tumor infiltrating depth, lymph node involvement, and pTNM stage. Low-scoring H3K9me3 and H4K20me3 predicted better prognosis, while H3K36me3 manifested the opposite trend. Poor prognosis occurred in ESCC patients with expression patterns of high levels of H3K9me3, high levels of H4K20me3, and low levels of H3K36me3 expression. CONCLUSIONS: H3K9me3, H4K20me3, and H3K36me3 showed a close relationship with clinical features and were considered independent risk factors for survival of ESCC patients. The combination of H3K9me3, H4K20me3, and H3K36me3 expression, rather than the expression of a single histone marker, is believed to further enhance evaluations of ESCC prognosis and management.
BACKGROUND: Histone methylation, as an essential pattern of posttranslational modifications, contributes to multiple cancer-related biological processes. Dysregulation of histone methylation is now considered a biomarker for cancer prognosis. AIMS: This study investigated and evaluated the potential role of four histone lysine trimethylation markers as biomarkers for esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: Tissue arrays were made from 135 paraffin-embedded ESCC samples and examined for histone markers by immunohistochemistry, and 10 pairs of cancer and noncancerous mucosa tissues from ESCC patients were investigated with Western blot. Chi-squared test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard trend analyses were performed to assess the prognostic values of the markers. RESULTS: Histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 4 lysine 20 trimethylation (H4K20me3), but not histone 3 lysine 36 trimethylation (H3K36me3), showed stronger immunostaining signals in tumor tissues than in the corresponding adjacent non-neoplastic mucosa tissues. The expression patterns of H3K36me3, H3K9me3, and H4K20me3 correlated with tumor infiltrating depth, lymph node involvement, and pTNM stage. Low-scoring H3K9me3 and H4K20me3 predicted better prognosis, while H3K36me3 manifested the opposite trend. Poor prognosis occurred in ESCC patients with expression patterns of high levels of H3K9me3, high levels of H4K20me3, and low levels of H3K36me3 expression. CONCLUSIONS: H3K9me3, H4K20me3, and H3K36me3 showed a close relationship with clinical features and were considered independent risk factors for survival of ESCC patients. The combination of H3K9me3, H4K20me3, and H3K36me3 expression, rather than the expression of a single histone marker, is believed to further enhance evaluations of ESCC prognosis and management.
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