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MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In addition, to confirm the involvement of NUSAP1 in the C28-mediated effect on microtubule stability and cell cycle arrest, we investigated the levels of cyclin-dependent kinase 1 (CDK1), a previously described NUSAP1-regulated protein [[12]], and phospho- III tubulin (S172). Taken together, although C28 can potentially bind tubulin, its relatively low binding affinity to purified tubulin dimer and the lack of any observable effect on tubulin polymerization suggest that C28 does not confer its effects by direct inhibition of tubulin polymerization. Considering the role of kinase inhibitors on microtubules [[4]], we investigated the possibility that C28 is a direct tubulin-targeting agent by employing an in vitro tubulin polymerization assay. Keywords: LMTK3; Kinase inhibitor; Breast cancer; Tubulin; NUSAP1 EN LMTK3 Kinase inhibitor Breast cancer Tubulin NUSAP1 1 6 6 04/12/21 20210409 NES 210409 The original online version of this article was revised: There are errors in Figures 2a and 2d. [Extracted from the article]