title: Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers.
abstract: Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis.
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Haitao
authors.initials: H
authors.lastname: Mao
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Zhenfang
authors.initials: Z
authors.lastname: Du
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Wai Yee
authors.initials: WY
authors.lastname: Chan
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Murray
authors.affiliation: Department of Medical Microbiology, Qingdao University Medical College, Shandong, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Luo
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Anthony Tc
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Tony Sk
authors.initials: TS
authors.lastname: Mok
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Diseases, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Francis Kl
authors.initials: FK
authors.lastname: Chan
authors.affiliation: Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.|Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D000072417:Protein Domains; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000098552:Slit Homolog 2 Protein
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C116326:ZNF382 protein, human; C097899:homeobox protein HOXA9; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D000098552:Slit Homolog 2 Protein