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.
Highlights
KIF14 was first identified as an oncogene and a contributor to malignant transformation in the childhood cancer retinoblastoma [1]
Our group and others have previously shown that KIF14 protein and mRNA are overexpressed in multiple cancers including ovarian cancers (OvCa tumors) [4,5,6,7,8,9,10]
Through siRNA knockdown and Chromatin Immunoprecipitation (ChIP) assays, we show that Sp1 and YY1, but not HSF1 directly bind to the KIF14 promoter and control endogenous KIF14 levels in OvCa cell lines
Summary
KIF14 was first identified as an oncogene and a contributor to malignant transformation in the childhood cancer retinoblastoma [1]. We reported that overall outcome of serous OvCa patients can be predicted based on KIF14 mRNA expression levels in their primary tumors Further analysis of these samples showed that expression of KIF14 mRNA and protein exceed the levels expected based on the copy number gain alone, suggesting an up-regulation in the transcriptional control in cancer cells versus their respective normal counterparts. Its cellular function has not yet been fully elucidated, KIF14 plays a vital role in the completion of cytokinesis, and may function in the primary cilium [11] It interacts with protein-regulator of cytokinesis 1 (PRC1) and citron kinase through specific domains to support proper cell division [12,13]. We recently demonstrated in breast cancer cells lines, direct interaction of KIF14 with Radil, a crucial mediator of Rap1a-mediated integrin inside-out signaling, thereby controlling Radil-Rap1a activity at the cell membrane and promoting cell adhesion and migration [14]
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