Li Y, etal., Cancer Biol Ther. 2015;16(9):1316-22. doi: 10.1080/15384047.2015.1070980. Epub 2015 Jul 15.
Kinesin-like protein KIFC1, a normally nonessential kinesin motor, plays a critical role in centrosome clustering in cancer cells and is essential for the survival of cancer cells. Herein, we reported that KIFC1 expression i
s up-regulated in breast cancer, particularly in estrogen receptor negative, progesterone receptor negative and triple negative breast cancer, and is not associated with epidermal growth factor receptor 2 status. In addition, KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. Moreover, KIFC1 silencing significantly reduced breast cancer cell viability. Finally, we found that PJ34, a potent small molecule inhibitor of poly(ADP-ribose) polymerase, suppressed KIFC1 expression and induced multipolar spindle formation in breast cancer cells, and inhibited cell viability and colony formation within the same concentration range, suggesting that KIFC1 suppression by PJ34 contributes to its anti-breast cancer activity. Together, these results suggest that KIFC1 is a novel promising therapeutic target for breast cancer.
Yang WX and Sperry AO, Biol Reprod 2003 Nov;69(5):1719-29. Epub 2003 Jun 25.
We have identified a possible role for the KIFC1 motor protein in formation of the acrosome, an organelle unique to spermatogenesis. KIFC1, a C-terminal kinesin motor, first appears on membrane-bounded organelles (MBOs) in t
he medulla of early spermatids followed by localization to the acrosomal vesicle. KIFC1 continues to be present on the acrosome of elongating spermatids as it flattens on the spermatid nucleus; however, increasing amounts of KIFC1 are found at the caudal aspect of the spermatid head and in distal cytoplasm. The KIFC1 motor is also found in the nucleus of very immature round spermatids just prior to its appearance on the acrosome. In some cases, KIFC1 appears localized just below the nuclear membrane adjacent to the subacrosomal membrane. We demonstrate that KIFC1 is associated with importin beta and colocalizes with this nuclear transport factor on curvilinear structures associated with the spermatid nuclei. These data support a model in which KIFC1, perhaps in association with nuclear factors, assists in the formation and/or elongation of the spermatid acrosome. This article represents the first demonstration of a direct association of a molecular motor with the spermatid acrosome, the formation of which is essential for fertilization.
BACKGROUND: Amplified centrosomes are widely recognized as a hallmark of cancer. Although supernumerary centrosomes would be expected to compromise cell viability by yielding multipolar spindles that results in death-inducing aneuploidy, cancer cells suppress multipolarity by clustering their extra
centrosomes. Thus, cancer cells, with the aid of clustering mechanisms, maintain pseudobipolar spindle phenotypes that are associated with low-grade aneuploidy, an edge to their survival. KIFC1, a nonessential minus end-directed motor of the kinesin-14 family, is a centrosome clustering molecule, essential for viability of extra centrosome-bearing cancer cells. Given that ovarian cancers robustly display amplified centrosomes, we examined the overexpression of KIFC1 in human ovarian tumors. RESULTS: We found that in clinical epithelial ovarian cancer (EOC) samples, an expression level of KIFC1 was significantly higher when compared to normal tissues. KIFC1 expression also increased with tumor grade. Our In silico analyses showed that higher KIFC1 expression was associated with poor overall survival (OS) in serous ovarian adenocarcinoma (SOC) patients suggesting that an aggressive disease course in ovarian adenocarcinoma patients can be attributed to high KIFC1 levels. Also, gene expression levels of KIFC1 in high-grade serous ovarian carcinoma (HGSOC) highly correlated with expression of genes driving centrosome amplification (CA), as examined in publically-available databases. The pathway analysis results indicated that the genes overexpressed in KIFC1 high group were associated with processes like regulation of the cell cycle and cell proliferation. In addition, when we performed gene set enrichment analysis (GSEA) for identifying the gene ontologies associated to KIFC1 high group, we found that the first 100 genes enriched in KIFC1 high group were from centrosome components, mitotic cell cycle, and microtubule-based processes. Results from in vitro experiments on well-established in vitro models of HGSOC (OVSAHO, KURAMOCHI), OVCAR3 and SKOV3) revealed that they display robust centrosome amplification and expression levels of KIFC1 was directly associated (inversely correlated) to the status of multipolar mitosis. This association of KIFC1 and centrosome amplification with HGSOC might be able to explain the increased aggressiveness in this disease. CONCLUSION: These findings compellingly underscore that KIFC1 can be a biomarker that predicts an aggressive disease course in ovarian adenocarcinomas.
Yang WX, etal., Biol Reprod. 2006 Apr;74(4):684-90. Epub 2005 Dec 21.
KIFC1 is a C-terminal kinesin motor associated with the nuclear membrane and acrosome in round and elongating spermatids. This location in developing spermatids is consistent with possible roles in acrosome elongation and manchette motility or both. Here we desc
ribe the association of the KIFC1 motor with a complex containing the nucleoporin NUP62. Formation of this complex is developmentally regulated, being absent before puberty and appearing only after nuclear elongation has begun. In addition, the integrity of this complex is dependent on GTP hydrolysis and the GTP state of the small GTPase RAN. Concomitant with the association of this motor with the NUP62-containing complex is an apparent reorganization of the nuclear pore with loss of NUP62 from larger complexes containing other nucleoporins. The association of KIFC1 with a component of the nuclear membrane is more consistent with a role for this motor in acrosome/manchette transport along the nuclear membrane than for a role for this motor in transport of vesicles along the outer face of the manchette.
