Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma

Abstract

Chromosome instability (CIN), the hallmarks of cancer, reflects ongoing chromosomal changes caused by chromosome segregation errors and results in whole chromosomal or segmental aneuploidy. In multiple myeloma (MM), CIN contributes to the acquisition of tumor heterogeneity, and thereby, to disease progression, drug resistance, and eventual treatment failure; however, the underlying mechanism of CIN in MM remains unclear. Faithful chromosomal segregation is tightly regulated by a series of mitotic checkpoint proteins, such as budding uninhibited by benzimidazoles 1 (BUB1). In this study, we found that BUB1 was overexpressed in patient-derived myeloma cells, and BUB1 expression was significantly higher in patients in an advanced stage compared to those in an early stage. This suggested the involvement of aberrant BUB1 overexpression in disease progression. In human myeloma-derived cell lines (HMCLs), BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells. In line with this, partial knockdown of BUB1 showed reduced variations in chromosome number compared to parent cells in HMCLs. Finally, BUB1 overexpression was found to promote the clonogenic potency of HMCLs. Collectively, these results suggested that enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in CIN in MM.

HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas

“…BUB1 is a central component of the mitotic checkpoint for spindle assembly, mediating cell death in response to chromosome missegregation and thus suppressing spontaneous tumorigenesis [ 61 ]. Although BUB1 seems to be a tumor suppressor, enhanced BUB1 expression causes chromosome instability and further induced oncogenesis [ 62 ]. Similar to CCNB2, BUB1 is also a hub protein in the NSCLC protein-protein interaction network and its overexpression is a poor prognostic indicator for NSCLC patients [ 59 , 63 ].…”

Prognostic Value of BUB1 for Predicting Non-Muscle-Invasive Bladder Cancer Progression

“…BUB1 gene levels were found to be overexpressed in the breast and gastric cancers, as well as in lymphomas [ 29 , 30 , 31 ]. BUB1 was identified as a prospective prognostic marker whose upregulation is associated with poor clinical outcomes in diverse tumor types [ 8 , 32 , 33 , 34 ]. These results support the value of the present study for explaining the role of BUB1 as an oncogene in BCa.…”

The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma

“…BUB1 mitotic checkpoint serine/threonine kinase (BUB1) is overexpressed in pancreatic ductal adenocarcinoma, which could be a useful parameter to predict the poor prognosis of pancreatic ductal adenocarcinoma (PDAC) [ 53 ]. Overexpression of BUB1 influences the progression of multiple myeloma by promoting mitotic segregation errors and chromosomal instability [ 54 ]. Therefore, BUB1 plays a significant role in the progression of many types of cancers in different ways, but it has been poorly investigated in the crosstalk between stromal cells and cancer cells.…”