Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer

Brigitte L. Thériault, Halesha D. Basavarajappa, Harvey Lim, Sanja Pajovic, Brenda L. Gallie, Timothy Corson

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Article numbere91540
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 13 2014

Fingerprint

Kinesin
kinesin
ovarian neoplasms
Epigenomics
epigenetics
Ovarian Neoplasms
Tumors
neoplasms
Neoplasms
Cells
promoter regions
MicroRNAs
microRNA
therapeutics
Transcription Factors
transcription factors
cell lines
Cell Line
Methylation
Nucleic Acid Regulatory Sequences

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Thériault, B. L., Basavarajappa, H. D., Lim, H., Pajovic, S., Gallie, B. L., & Corson, T. (2014). Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer. PLoS One, 9(3), [e91540]. https://doi.org/10.1371/journal.pone.0091540

Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer. / Thériault, Brigitte L.; Basavarajappa, Halesha D.; Lim, Harvey; Pajovic, Sanja; Gallie, Brenda L.; Corson, Timothy.

In: PLoS One, Vol. 9, No. 3, e91540, 13.03.2014.

Research output: Contribution to journalArticle

Thériault, BL, Basavarajappa, HD, Lim, H, Pajovic, S, Gallie, BL & Corson, T 2014, 'Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer', PLoS One, vol. 9, no. 3, e91540. https://doi.org/10.1371/journal.pone.0091540
Thériault, Brigitte L. ; Basavarajappa, Halesha D. ; Lim, Harvey ; Pajovic, Sanja ; Gallie, Brenda L. ; Corson, Timothy. / Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer. In: PLoS One. 2014 ; Vol. 9, No. 3.
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