Hong-Chang Chen1, Hsuan-Yuan Huang1, Yao-Li Chen2,3, Kuan-Der Lee4,5, Yi-Ru Chu4,5,6, Ping-Yi Lin2, Chia-Chen Hsu6, Pei-Yi Chu7, Tim H-M Huang8, Shu-Huei Hsiao6, Yu-Wei Leu9. 1. Division of Colorectal Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan. 2. Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan. 3. School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 4. Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Chang Gung University College of Medicine, Taoyuan, Taiwan. 5. Chang Gung Institute of Technology, Taoyuan, Taiwan. 6. Department of Life Science, Human Epigenomics Center, Institute of Molecular Biology and Institute of Biomedical Science, National Chung Cheng University, Chia-Yi, Taiwan. 7. Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan. 8. Department of Molecular Medicine and Institute of Biotechnology, School of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. 9. Department of Life Science, Human Epigenomics Center, Institute of Molecular Biology and Institute of Biomedical Science, National Chung Cheng University, Chia-Yi, Taiwan. bioywl@ccu.edu.tw.
Abstract
BACKGROUND: Methylation changes within tumor suppressor (TS) genes or polycomb group target (PcG) genes alter cell fates. Chromatin associated with PcG targets is bivalent in stem cells, while TS genes are not normally bivalent. PcG target methylation changes have been identified in tumor stem cells, and abnormal methylation is found in TS genes in cancers. If the epigenetic states of genes influence DNA methylation, then methylation of PcG targets and TS genes may evolve differently during cancer development. More importantly, methylation changes may be part of a sequence in tumorigenesis. METHODS: Chromatin and methylation states of 4 PcG targets and 2 TS genes were determined in colon cancer cells. The methylation states were also detected in 100 pairs of colon cancer samples. Principle component analysis (PCA) was used to reveal whether TS methylation or PcG methylation was the main methylation change associated with colon cancers. RESULTS: Chromatin and methylation states differ in colon cancer cell lines. The methylation states within PcG targets clustered independently from the methylation states in TS genes, a finding we previously reported in liver cancers. PCA in colon cancers revealed the strongest association with methylation changes in 2 TS genes, HIC1 and RassF1A. Loss of HIC1 methylation correlated with decreased tumor migration. CONCLUSIONS: PcG and TS methylation states cluster independently from each other. The deduced principle component correlated better with TS methylation than PcG methylation in colon cancer. Abnormal methylation changes may represent a sequential biomarker profile to identify developing colon cancer.
BACKGROUND: Methylation changes within tumor suppressor (TS) genes or polycomb group target (PcG) genes alter cell fates. Chromatin associated with PcG targets is bivalent in stem cells, while TS genes are not normally bivalent. PcG target methylation changes have been identified in tumor stem cells, and abnormal methylation is found in TS genes in cancers. If the epigenetic states of genes influence DNA methylation, then methylation of PcG targets and TS genes may evolve differently during cancer development. More importantly, methylation changes may be part of a sequence in tumorigenesis. METHODS: Chromatin and methylation states of 4 PcG targets and 2 TS genes were determined in colon cancer cells. The methylation states were also detected in 100 pairs of colon cancer samples. Principle component analysis (PCA) was used to reveal whether TS methylation or PcG methylation was the main methylation change associated with colon cancers. RESULTS: Chromatin and methylation states differ in colon cancer cell lines. The methylation states within PcG targets clustered independently from the methylation states in TS genes, a finding we previously reported in liver cancers. PCA in colon cancers revealed the strongest association with methylation changes in 2 TS genes, HIC1 and RassF1A. Loss of HIC1 methylation correlated with decreased tumor migration. CONCLUSIONS:PcG and TS methylation states cluster independently from each other. The deduced principle component correlated better with TS methylation than PcG methylation in colon cancer. Abnormal methylation changes may represent a sequential biomarker profile to identify developing colon cancer.