BUBR1 (BUB1-related kinase) is a crucial protein involved in the mitotic checkpoint, which ensures proper chromosome segregation during cell division. BUBR1 is part of the spindle assembly checkpoint (SAC) that prevents aneuploidy by inhibiting the onset of anaphase until all chromosomes are correctly attached to the spindle apparatus.
Aberrations in BUBR1 function have been linked to
cancer development. Mutations or reduced expression of BUBR1 can lead to chromosomal instability (CIN), which is a hallmark of various cancers. CIN results in an unequal distribution of chromosomes to daughter cells, contributing to tumorigenesis and cancer progression.
Studies have shown that BUBR1 expression is often downregulated in many types of cancer, including
colorectal cancer,
breast cancer, and
lung cancer. This downregulation can be due to genetic mutations, epigenetic modifications, or transcriptional repression. Conversely, overexpression of BUBR1 has also been observed in certain cancers, suggesting a complex role in tumor biology.
The status of BUBR1 can serve as a prognostic marker in various cancers. Low levels of BUBR1 are often associated with poor prognosis and aggressive tumor behavior. Additionally, targeting the BUBR1 pathway has therapeutic potential. For instance,
inhibitors of the spindle assembly checkpoint are being explored as anti-cancer agents, aiming to exploit the vulnerabilities of cancer cells with defective mitotic checkpoints.
BUBR1 interacts with several key proteins involved in the cell cycle and mitosis. It forms a complex with
BUB3,
MAD2, and
CDC20 to inhibit the anaphase-promoting complex/cyclosome (APC/C) until all chromosomes are correctly attached to the spindle. These interactions are critical for maintaining genomic stability and preventing premature progression into anaphase.
Given its pivotal role in maintaining chromosomal stability, therapeutic strategies targeting BUBR1 are being developed. These include small molecule inhibitors that disrupt its function and
gene therapy approaches to restore its expression in cancers with reduced BUBR1 levels. Additionally, combination therapies that target BUBR1 along with other cell cycle regulators are being explored to enhance cancer treatment efficacy.
One of the main challenges in targeting BUBR1 is its dual role in cancer. While loss of BUBR1 function can promote cancer, its overexpression can also be detrimental. Therefore, therapeutic strategies need to be carefully tailored to the specific context of BUBR1 expression in different cancers. Moreover, potential side effects due to the disruption of normal mitotic processes in healthy cells must be considered.
Conclusion
BUBR1 is a critical player in the maintenance of genomic integrity, and its dysfunction is closely linked to cancer. Understanding the complex role of BUBR1 in different types of cancer can lead to the development of novel therapeutic strategies. Future research should focus on elucidating the precise mechanisms by which BUBR1 contributes to cancer and identifying effective ways to target this protein for cancer treatment.
