Chang-Lin Hsieh1, Hon-Ping Ma2, Chih-Ming Su3, Yu-Jia Chang4, Wan-Yu Hung5, Yuan-Soon Ho6, Wei-Jan Huang7, Ruo-Kai Lin8. 1. Professional Master Program in Pharmaceutics and Biotechnology, Taipei Medical University, Taipei 110, Taiwan, ROC. 2. Emergency Department, Shuang Ho Hospital, New Taipei City 235, Taiwan, ROC; Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC. 3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC; Department of Surgery, Taipei Medical University Shuang Ho Hospital, Taipei 235, Taiwan, ROC. 4. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC. 5. Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei 110, Taiwan, ROC. 6. Graduate Institute of Biomedical Technology, Comprehensive Cancer Center, Taipei Medical University, Taipei 110, Taiwan, ROC. 7. Graduate Institute of Pharmacognosy, Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 110, Taiwan, ROC. 8. Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei 110, Taiwan, ROC; Graduate Institute of Pharmacognosy, Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 110, Taiwan, ROC. Electronic address: linruokai@tmu.edu.tw.
Abstract
AIMS: Alterations in histone proteins can lead to breast tumorigenesis. Selective histone deacetylase 8 (HDAC8) inhibitors with fewer adverse effects have been developed. A more comprehensive study of alterations and its mechanisms in HDAC8 is required. In this study, we investigated mechanisms of dysregulation of HDAC8 expression and its biological role and pathways in breast cancer. MAIN METHODS: Alterations in HDAC8 were analyzed in Taiwanese breast cancer patients; and in tissue samples from The Cancer Genome Atlas (TCGA) data set that were derived from Western countries. Knockdown by si-HDAC8, treatment with the HDAC8-specific inhibitor PCI-34051, SRB assays, wound healing, Transwell migration assays, Illumina BeadArray™ arrays and Ingenuity Pathway Analysis (IPA) were performed in breast cancer cells. KEY FINDINGS: HDAC8 mRNA expression was upregulated in paired breast cancer tissue from Taiwanese patients and in paired breast cancer tissues from the TCGA data set. Hypomethylation of promoter regions was significantly correlated with HDAC8 mRNA overexpression in 588 breast cancer patients from the TCGA data set and was associated with poor prognosis in early-stage breast cancer. HDAC8 mRNA overexpression was associated with late stages and tumor progression. Wound healing and Transwell migration assays revealed that knockdown by si-HDAC8 or PCI-34051 treatment significantly inhibited breast cancer cell migration. Knockdown by si-HDAC8, Illumina BeadArray™ arrays and IPA found that ID3 and PTP4A2 pathways were regulated by HDAC8 in cancer cell migration. SIGNIFICANCE: Hypomethylation of the HDAC8 promoter is correlated with HDAC8 overexpression and breast cancer progression and is a potential prognosis marker and drug target.
AIMS: Alterations in histone proteins can lead to breast tumorigenesis. Selective histone deacetylase 8 (HDAC8) inhibitors with fewer adverse effects have been developed. A more comprehensive study of alterations and its mechanisms in HDAC8 is required. In this study, we investigated mechanisms of dysregulation of HDAC8 expression and its biological role and pathways in breast cancer. MAIN METHODS: Alterations in HDAC8 were analyzed in Taiwanese breast cancerpatients; and in tissue samples from The Cancer Genome Atlas (TCGA) data set that were derived from Western countries. Knockdown by si-HDAC8, treatment with the HDAC8-specific inhibitor PCI-34051, SRB assays, wound healing, Transwell migration assays, Illumina BeadArray™ arrays and Ingenuity Pathway Analysis (IPA) were performed in breast cancer cells. KEY FINDINGS:HDAC8 mRNA expression was upregulated in paired breast cancer tissue from Taiwanese patients and in paired breast cancer tissues from the TCGA data set. Hypomethylation of promoter regions was significantly correlated with HDAC8 mRNA overexpression in 588 breast cancerpatients from the TCGA data set and was associated with poor prognosis in early-stage breast cancer. HDAC8 mRNA overexpression was associated with late stages and tumor progression. Wound healing and Transwell migration assays revealed that knockdown by si-HDAC8 or PCI-34051 treatment significantly inhibited breast cancer cell migration. Knockdown by si-HDAC8, Illumina BeadArray™ arrays and IPA found that ID3 and PTP4A2 pathways were regulated by HDAC8 in cancer cell migration. SIGNIFICANCE: Hypomethylation of the HDAC8 promoter is correlated with HDAC8 overexpression and breast cancer progression and is a potential prognosis marker and drug target.
Authors: Thomas W Hanigan; Shaimaa M Aboukhatwa; Taha Y Taha; Jonna Frasor; Pavel A Petukhov Journal: Cell Chem Biol Date: 2017-09-21 Impact factor: 8.116
Authors: Taha Y Taha; Shaimaa M Aboukhatwa; Rachel C Knopp; Naohiko Ikegaki; Hazem Abdelkarim; Jayaprakash Neerasa; Yunlong Lu; Raghupathi Neelarapu; Thomas W Hanigan; Gregory R J Thatcher; Pavel A Petukhov Journal: ACS Med Chem Lett Date: 2017-08-01 Impact factor: 4.345