title: A mathematical model of bimodal epigenetic control of miR-193a in ovarian cancer stem cells.
abstract: Accumulating data indicate that cancer stem cells contribute to tumor chemoresistance and their persistence alters clinical outcome. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by surface antigen CD44 and c-KIT (CD117). It has been experimentally demonstrated that a microRNA, namely miR-193a, targets c-KIT mRNA for degradation and could play a crucial role in ovarian cancer development. How miR-193a is regulated is poorly understood and the emerging picture is complex. To unravel this complexity, we propose a mathematical model to explore how estrogen-mediated up-regulation of another target of miR-193a, namely E2F6, can attenuate the function of miR-193a in two ways, one through a competition of E2F6 and c-KIT transcripts for miR-193a, and second by binding of E2F6 protein, in association with a polycomb complex, to the promoter of miR-193a to down-regulate its transcription. Our model predicts that this bimodal control increases the expression of c-KIT and that the second mode of epigenetic regulation is required to generate a switching behavior in c-KIT and E2F6 expressions. Additional analysis of the TCGA ovarian cancer dataset demonstrates that ovarian cancer patients with low expression of EZH2, a polycomb-group family protein, show positive correlation between E2F6 and c-KIT. We conjecture that a simultaneous EZH2 inhibition and anti-estrogen therapy can constitute an effective combined therapeutic strategy against ovarian cancer.
authors.affiliation: Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Frank H C
authors.initials: FH
authors.lastname: Cheng
authors.affiliation: DiseasePathways LLC, Bethesda, Maryland, United States of America.
authors.forename: Baltazar D
authors.initials: BD
authors.lastname: Aguda
authors.affiliation: Department of Mathematics, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Je-Chiang
authors.initials: JC
authors.lastname: Tsai
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Kochańczyk
authors.affiliation: Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Jora M J
authors.initials: JM
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Gary C W
authors.initials: GC
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China; Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China; Institute of Clinical Pharmacology, Central South University, Changsha, People's Republic of China; Hunan Key Laboratory of Pharmacogenetics, Changsha, People's Republic of China.
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Medical Sciences, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, Indiana, United States of America.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.affiliation: Department of Mathematics, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Tzy-Wei
authors.initials: TW
authors.lastname: Hwang
authors.affiliation: Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D050701:E2F6 Transcription Factor / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D050701:E2F6 Transcription Factor; C491744:E2F6 protein, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D019009:Proto-Oncogene Proteins c-kit