title: Integrative epigenome analysis identifies a Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in colorectal cancer.
abstract: Aberrant DNA hypermethylation in human cancer has been associated with Polycomb target genes in embryonic stem (ES) cells, but a functional link of the Polycomb-targeted differentiation program to tumorigenesis remains to be established. Here, through epigenome analysis correlating DNA hypermethylation in colon cancer with ES cell pluripotency and differentiation, we identified a set of DNA hypermethylated genes in cancer cells that are Polycomb targets strongly associated with ES cell differentiation, including HAND1, a developmental regulator. Intriguingly, HAND1 is silenced in over 90% of human primary colorectal tumors, and re-expression of HAND1 in colon cancer cells induces terminal differentiation, inhibits proliferation and prevents xenograft tumor formation. Moreover, hypermethylated HAND1 has a minimum enrichment of EZH2-H3K27me3 in cancer cells, but becomes EZH2 bound and bivalent upon the loss of DNA methylation, suggesting a sequential gene silencing event during oncogenesis. These findings established a functional role of Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in human cancer.
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: P L
authors.initials: PL
authors.lastname: Lee
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: 1] Stem Cell and Developmental Biology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore [2] Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Robson
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: Q
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones; D063151:Polycomb Repressive Complex 2; C097341:helix-loop-helix protein, eHAND; C498409:EZH2 protein, human