title: Epigenetic up-regulation of leukemia inhibitory factor (LIF) gene during the progression to breast cancer.
abstract: The interleukin 6 family of cytokines including leukemia inhibitory factor (LIF) regulates the progression of several types of cancer. However, although LIF overexpression during breast cancer progression was observed in our previous report, the molecular mechanisms responsible for this deregulation remain largely unknown. Here we show that LIF expression is epigenetically up-regulated via DNA demethylation and changes in histone methylation status within its promoter region in the isogenic MCF10 model. Bisulfite sequencing revealed the CpG pairs within the promoter region are hypermethylated in normal breast epithelial cells, but extensively demethylated as breast cancer progresses. In agreement with the DNA methylation pattern, our chromatin immunoprecipitation showed that inactive epigenetic marks such as MeCP2 occupancy and histone H3-Lys9-dimethylation significantly decreased during the progression to breast cancer but an active histone mark was increased in an inverse manner. Also, the occupancy of the transcription factor Sp1, which has higher affinity for hypomethylated CpGs, increased. RNAi-mediated knockdown of LIF expression resulted in a significant reduction of cell growth and colony formation in breast cancer cells, suggesting the potential role of LIF-LIF receptor axis in autocrine stimulation of cancer cells. Collectively, our data suggest that the epigenetic up-regulation of the LIF gene likely play an important role in the development of breast cancer.
authors.affiliation: Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Shin
authors.forename: Su Hyung
authors.initials: SH
authors.lastname: Park
authors.forename: Yeun Kyu
authors.initials: YK
authors.lastname: Jang
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D008969:Molecular Sequence Data; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D006657:Histones; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D001374:Azacitidine