Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy.

Patrick Wolter,Stefan Gaubatz,Grit Pattschull,Steffen Hanselmann,Eva Schruf

doi:10.18632/oncotarget.14466

Abstract

The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells. Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.

Highlights

Cell cycle regulation is essential for normal development and, when disturbed, can lead to a number of diseases such as cancer
Unspecific IgG was used as a control. qPCR analysis was used to analyze binding to the promoters of 15 kinesins with suggested functions in mitosis and cytokinesis
LIN9, B-MYB and FOXM1 strongly bound to the promoters of 8 of 15 mitotic kinesins (KIF14, KIF20A, KIF11, KIF4A, KIF20B, KIF23, KIF10, KIF22) and to the PRC1 promoter

Summary

Introduction

Cell cycle regulation is essential for normal development and, when disturbed, can lead to a number of diseases such as cancer. MuvB is an evolutionary conserved multisubunit complex that regulates gene expression during the cell cycle (reviewed in [1]). MuvB, consisting of the five proteins LIN9, LIN37, LIN52, LIN54 and RBBP4, associates with the p130 retinoblastoma protein paralogue and with E2F4 and DP1 to form DREAM, which represses cell cycle genes in quiescence and early G1 [2, 3]. In S phase, the interaction of the MuvB core with p130/E2F4/DP1 is lost and MuvB binds to the B-MYB (MYBL2) transcription factor to form the Myb-MuvB complex ( called MMB) [2, 4,5,6]. Mice with disrupted MuvB function die early during development due to a defect in implantation [8, 13]

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