title: Restoration of IGF2 imprinting by polycomb repressive complex 2 docking factor SUZ12 in colon cancer cells.
abstract: The insulin-like growth factor II (IGF2) gene is aberrantly expressed in tumors as a result of loss of imprinting (LOI). Reactivation of the normally-suppressed maternal allele may lead to IGF2 upregulation and increased tumor growth, particularly in colon cancer. However, the mechanisms underlying IGF2 LOI in tumors are poorly defined. In this report, we identified polycomb repressive complex 2 (PRC2) docking factor SUZ12 as a critical factor in regulating IGF2 imprinting in tumors. Human colon cancer cell lines (HRT18 and HT29) show loss of IGF2 imprinting. Ectopic expression of SUZ12 restored normal monoallelic expression of IGF2 in these two colon cancer cell lines. Using chromatin immunoprecipitation (ChIP) and chromatin conformation capture (3C), we found that the virally-expressed SUZ12 bound to IGF2 promoters, coordinating with endogenous CTCF to orchestrate a long range intrachromosomal loop between the imprinting control region (ICR) and the IGF2 promoters. The histone methyltransferase EZH2 was recruited to the IGF2 promoters, where it induced H3K27 hypermethylation, suppressing one allele, leading to the restoration of IGF2 imprinting. These data demonstrate that SUZ12 is a key molecule in the regulation of monoallelic expression of IGF2, suggesting a novel epigenetic therapeutic strategy for modulating IGF2 production in human tumors.
authors.affiliation: Institute of Cardiovascular Diseases, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China; Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Ge
authors.affiliation: Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Guanxiang
authors.initials: G
authors.lastname: Qian
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Jiuwei
authors.initials: J
authors.lastname: Cui
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Wang
authors.affiliation: Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: arhoffman@stanford.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffman
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China; Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: jifan@stanford.edu.
authors.forename: Ji-Fan
authors.initials: JF
authors.lastname: Hu
mesh_terms: D000483:Alleles; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003110:Colonic Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D019073:HT29 Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors
chemical_list: D006657:Histones; C035170:IGF2 protein, human; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II; D063151:Polycomb Repressive Complex 2
keywords: CTCF; Epigenetics; Histone K27 methylation; IGF2 imprinting; Intrachromosomal loop; Polycomb repressive complex 2; Promoter; SUZ12