title: Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer.
abstract: KIF14 (kinesin family member 14) is a mitotic kinesin and an important oncogene in several cancers. Tumor KIF14 expression levels are independently predictive of poor outcome, and in cancer cells KIF14 can modulate metastatic behavior by maintaining appropriate levels of cell adhesion and migration proteins at the cell membrane. Thus KIF14 is an exciting potential therapeutic target. Understanding KIF14's regulation in cancer cells is crucial to the development of effective and selective therapies to block its tumorigenic function(s). We previously determined that close to 30% of serous ovarian cancers (OvCa tumors) exhibit low-level genomic gain, indicating one mechanism of KIF14 overexpression in tumors. We now report on transcriptional and epigenetic regulation of KIF14. Through promoter deletion analyses, we identified one cis-regulatory region containing binding sites for Sp1, HSF1 and YY1. siRNA-mediated knockdown of these transcription factors demonstrated endogenous regulation of KIF14 overexpression by Sp1 and YY1, but not HSF1. ChIP experiments confirmed an enrichment of both Sp1 and YY1 binding to the endogenous KIF14 promoter in OvCa cell lines with high KIF14 expression. A strong correlation was seen in primary serous OvCa tumors between Sp1, YY1 and KIF14 expression, further evidence that these transcription factors are important players in KIF14 overexpression. Hypomethylation patterns were observed in primary serous OvCa tumors, suggesting a minor role for promoter methylation in the control of KIF14 gene expression. miRNA expression analysis determined that miR-93, miR-144 and miR-382 had significantly lower levels of expression in primary serous OvCa tumors than normal tissues; treatment of an OvCa cell line with miRNA mimics and inhibitors specifically modulated KIF14 mRNA levels, pointing to potential novel mechanisms of KIF14 overexpression in primary tumors. Our findings reveal multiple mechanisms of KIF14 upregulation in cancer cells, offering new targets for therapeutic interventions to reduce KIF14 in tumors, aiming at improved prognosis.
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Thériault
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Halesha D
authors.initials: HD
authors.lastname: Basavarajappa
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Harvey
authors.initials: H
authors.lastname: Lim
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Sanja
authors.initials: S
authors.lastname: Pajovic
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Visual Science, Toronto Western Hospital Research Institute, Toronto, Ontario, Canada; Departments of Molecular Genetics and Ophthalmology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Gallie
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Corson
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C502598:KIF14 protein, human; D016547:Kinesins