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H3K9me3, H3K36me3, and H4K20me3 Expression Correlates with Patient Outcome in Esophageal Squamous Cell Carcinoma as Epigenetic Markers

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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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81672414 and 81472548) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_0058). This work was also supported by the Innovation Capability Development Project of Jiangsu Province (BM2015004) and the Key Project of Cutting-edge Clinical Technology of Jiangsu Province (BE2017759).

Author information

Author notes

  1. Menghan Zhou, Yiping Li, and Shaofeng Lin have contributed equally to this work.

Authors and Affiliations

  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

    Menghan Zhou, Yanyan Qian, Zhujiang Zhao & Hong Fan

  2. Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, 210018, China

    Menghan Zhou

  3. Department of Pathology, Medical School, Southeast University, Nanjing, 210009, China

    Yiping Li

  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

    Shaofeng Lin

  5. Department of Oncology, Fujian Provincial Cancer Hospital, Fuzhou, 350000, China

    Shaofeng Lin

  6. Department of Pathology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China

    Yanping Chen

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  1. Menghan Zhou
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Correspondence to Hong Fan.

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10620_2019_5529_MOESM1_ESM.jpg

Figure S1. Scales of staining intensity for the stained histone markers by the IHC assay. I0 = negative (no staining); I1 = weak staining; I2 = moderate staining; and I3 = intensive staining. (JPEG 4665 kb)

10620_2019_5529_MOESM2_ESM.jpg

Figure S2. Scales of staining area for the stained histone markers by the IHC technique. Based on the percentage of labeled cells in the observed epithelial tissues, 5 different levels were defined as follows: A0 = 0~5% positive cells; A1 = 6~25% positive cells; A2 = 26~50% positive cells; A3 = 51~75% positive cells; and A4 = 76~100% positive cells. (JPEG 6481 kb)

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Zhou, M., Li, Y., Lin, S. et al. H3K9me3, H3K36me3, and H4K20me3 Expression Correlates with Patient Outcome in Esophageal Squamous Cell Carcinoma as Epigenetic Markers. Dig Dis Sci 64, 2147–2157 (2019). https://doi.org/10.1007/s10620-019-05529-2

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