Transcriptional and Epigenetic Regulation of <i>KIF14</i> Overexpression in Ovarian Cancer

<div><p><i>KIF14</i> (kinesin family member 14) is a mitotic kinesin and an important oncogene in several cancers. Tumor <i>KIF14</i> 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 <i>KIF14</i> overexpression in tumors. We now report on transcriptional and epigenetic regulation of <i>KIF14</i>. Through promoter deletion analyses, we identified one <i>cis</i>-regulatory region containing binding sites for Sp1, HSF1 and YY1. siRNA-mediated knockdown of these transcription factors demonstrated endogenous regulation of <i>KIF14</i> overexpression by <i>Sp1</i> and <i>YY1</i>, but not <i>HSF1</i>. ChIP experiments confirmed an enrichment of both Sp1 and YY1 binding to the endogenous KIF14 promoter in OvCa cell lines with high <i>KIF14</i> expression. A strong correlation was seen in primary serous OvCa tumors between <i>Sp1</i>, <i>YY1</i> and <i>KIF14</i> expression, further evidence that these transcription factors are important players in <i>KIF14</i> overexpression. Hypomethylation patterns were observed in primary serous OvCa tumors, suggesting a minor role for promoter methylation in the control of <i>KIF14</i> 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 <i>KIF14</i> mRNA levels, pointing to potential novel mechanisms of <i>KIF14</i> 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.</p>