Young Min Lee1, Seok Hyun Kim2, Minseok S Kim3, Dae Cheol Kim4, Eun Hee Lee5, Ju Suk Lee6, Sung-Hun Lee7, Young Zoon Kim1. 1. Division of Neuro Oncology, Department of Neurosurgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea. 2. Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea. 3. Department 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, Korea. 4. Department of Pathology, Dong-A University Hospital, Dong-A University College of Medicine, Busan 49201, Korea. 5. Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea. 6. Department of Pediatrics, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea. 7. Cancer Research Institute, Clinomics Inc., Suwon 16229, Korea.
Abstract
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%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 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.
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%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 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.
Entities:
Keywords:
brain metastasis; epigenome; epithelial-to-mesenchymal transition; histone modification; lung cancer
Authors: Jianxun Wang; Kathleen Scully; Xiaoyan Zhu; Ling Cai; Jie Zhang; Gratien G Prefontaine; Anna Krones; Kenneth A Ohgi; Ping Zhu; Ivan Garcia-Bassets; Forrest Liu; Havilah Taylor; Jean Lozach; Friederike L Jayes; Kenneth S Korach; Christopher K Glass; Xiang-Dong Fu; Michael G Rosenfeld Journal: Nature Date: 2007-03-28 Impact factor: 49.962
Authors: Paul W Sperduto; Norbert Kased; David Roberge; Zhiyuan Xu; Ryan Shanley; Xianghua Luo; Penny K Sneed; Samuel T Chao; Robert J Weil; John Suh; Amit Bhatt; Ashley W Jensen; Paul D Brown; Helen A Shih; John Kirkpatrick; Laurie E Gaspar; John B Fiveash; Veronica Chiang; Jonathan P S Knisely; Christina Maria Sperduto; Nancy Lin; Minesh Mehta Journal: J Clin Oncol Date: 2011-12-27 Impact factor: 44.544
Authors: Sooryanarayana Varambally; Saravana M Dhanasekaran; Ming Zhou; Terrence R Barrette; Chandan Kumar-Sinha; Martin G Sanda; Debashis Ghosh; Kenneth J Pienta; Richard G A B Sewalt; Arie P Otte; Mark A Rubin; Arul M Chinnaiyan Journal: Nature Date: 2002-10-10 Impact factor: 49.962