Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma
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 p...
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2206 |
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| author | Yuto Fujibayashi Reiko Isa Daichi Nishiyama Natsumi Sakamoto-Inada Norichika Kawasumi Junko Yamaguchi Saeko Kuwahara-Ota Yayoi Matsumura-Kimoto Taku Tsukamoto Yoshiaki Chinen Yuji Shimura Tsutomu Kobayashi Shigeo Horiike Masafumi Taniwaki Hiroshi Handa Junya Kuroda |
| author_facet | Yuto Fujibayashi Reiko Isa Daichi Nishiyama Natsumi Sakamoto-Inada Norichika Kawasumi Junko Yamaguchi Saeko Kuwahara-Ota Yayoi Matsumura-Kimoto Taku Tsukamoto Yoshiaki Chinen Yuji Shimura Tsutomu Kobayashi Shigeo Horiike Masafumi Taniwaki Hiroshi Handa Junya Kuroda |
| author_sort | Yuto Fujibayashi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:51:51Z |
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| language | English |
| last_indexed | 2024-03-10T17:51:51Z |
| publishDate | 2020-08-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-74be6ffa7dff478f8852d610666d402d2023-11-20T09:19:53ZengMDPI AGCancers2072-66942020-08-01128220610.3390/cancers12082206Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple MyelomaYuto Fujibayashi0Reiko Isa1Daichi Nishiyama2Natsumi Sakamoto-Inada3Norichika Kawasumi4Junko Yamaguchi5Saeko Kuwahara-Ota6Yayoi Matsumura-Kimoto7Taku Tsukamoto8Yoshiaki Chinen9Yuji Shimura10Tsutomu Kobayashi11Shigeo Horiike12Masafumi Taniwaki13Hiroshi Handa14Junya Kuroda15Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanDepartment of Hematology, Gunma University Graduate School of Medicine, Gunma 371-8511, JapanDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanChromosome 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.https://www.mdpi.com/2072-6694/12/8/2206multiple myelomaBUB1chromosome segregation errorchromosomal instabilityclonogenicity |
| spellingShingle | Yuto Fujibayashi Reiko Isa Daichi Nishiyama Natsumi Sakamoto-Inada Norichika Kawasumi Junko Yamaguchi Saeko Kuwahara-Ota Yayoi Matsumura-Kimoto Taku Tsukamoto Yoshiaki Chinen Yuji Shimura Tsutomu Kobayashi Shigeo Horiike Masafumi Taniwaki Hiroshi Handa Junya Kuroda Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma Cancers multiple myeloma BUB1 chromosome segregation error chromosomal instability clonogenicity |
| title | Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma |
| title_full | Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma |
| title_fullStr | Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma |
| title_full_unstemmed | Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma |
| title_short | Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma |
| title_sort | aberrant bub1 overexpression promotes mitotic segregation errors and chromosomal instability in multiple myeloma |
| topic | multiple myeloma BUB1 chromosome segregation error chromosomal instability clonogenicity |
| url | https://www.mdpi.com/2072-6694/12/8/2206 |
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