Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain
Purpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired...
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MDPI AG
2020-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/12/3632 |
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| author | Young Min Lee Seok Hyun Kim Minseok S. Kim Dae Cheol Kim Eun Hee Lee Ju Suk Lee Sung-Hun Lee Young Zoon Kim |
| author_facet | Young Min Lee Seok Hyun Kim Minseok S. Kim Dae Cheol Kim Eun Hee Lee Ju Suk Lee Sung-Hun Lee Young Zoon Kim |
| author_sort | Young Min Lee |
| collection | DOAJ |
| description | Purpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. Results: The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, <i>p</i> = 0.005), Twist (23.6% vs. 45.9%, <i>p</i> = 0.010) and ZEB1 (15.0% vs. 55.9%, <i>p</i> = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, <i>p</i> = 0.018) and H3K36me3 demethylase (UTX, <i>p</i> = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, <i>p</i> = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (<i>R</i><sup>2</sup> linear = 1.204) and MLL4-Slug (<i>R</i><sup>2</sup> linear = 0.987) was increased in direct proportion, and EZH2-Twist (<i>R</i><sup>2</sup> linear = −2.723) decreased in reverse proportion. Conclusions: The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain. |
| first_indexed | 2024-03-10T14:20:24Z |
| format | Article |
| id | doaj.art-574de8cf0a434986971dcee185c0c428 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:20:24Z |
| publishDate | 2020-12-01 |
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| series | Cancers |
| spelling | doaj.art-574de8cf0a434986971dcee185c0c4282023-11-20T23:27:40ZengMDPI AGCancers2072-66942020-12-011212363210.3390/cancers12123632Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the BrainYoung Min Lee0Seok Hyun Kim1Minseok S. Kim2Dae Cheol Kim3Eun Hee Lee4Ju Suk Lee5Sung-Hun Lee6Young Zoon Kim7Division of Neuro Oncology, Department of Neurosurgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, KoreaDivision of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, KoreaDepartment of New Biology, Well Aging Research Center, College of Transdisciplinary Studies, and Translational Responsive Medicine Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, KoreaDepartment of Pathology, Dong-A University Hospital, Dong-A University College of Medicine, Busan 49201, KoreaDepartment of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, KoreaDepartment of Pediatrics, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, KoreaCancer Research Institute, Clinomics Inc., Suwon 16229, KoreaDivision of Neuro Oncology, Department of Neurosurgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, KoreaPurpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. Results: The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, <i>p</i> = 0.005), Twist (23.6% vs. 45.9%, <i>p</i> = 0.010) and ZEB1 (15.0% vs. 55.9%, <i>p</i> = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, <i>p</i> = 0.018) and H3K36me3 demethylase (UTX, <i>p</i> = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, <i>p</i> = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (<i>R</i><sup>2</sup> linear = 1.204) and MLL4-Slug (<i>R</i><sup>2</sup> linear = 0.987) was increased in direct proportion, and EZH2-Twist (<i>R</i><sup>2</sup> linear = −2.723) decreased in reverse proportion. Conclusions: The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.https://www.mdpi.com/2072-6694/12/12/3632lung cancerbrain metastasisepigenomehistone modificationepithelial-to-mesenchymal transition |
| spellingShingle | Young Min Lee Seok Hyun Kim Minseok S. Kim Dae Cheol Kim Eun Hee Lee Ju Suk Lee Sung-Hun Lee Young Zoon Kim Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain Cancers lung cancer brain metastasis epigenome histone modification epithelial-to-mesenchymal transition |
| title | Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain |
| title_full | Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain |
| title_fullStr | Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain |
| title_full_unstemmed | Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain |
| title_short | Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain |
| title_sort | epigenetic role of histone lysine methyltransferase and demethylase on the expression of transcription factors associated with the epithelial to mesenchymal transition of lung adenocarcinoma metastasis to the brain |
| topic | lung cancer brain metastasis epigenome histone modification epithelial-to-mesenchymal transition |
| url | https://www.mdpi.com/2072-6694/12/12/3632 |
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