Expanding roles of centrosome abnormalities in cancers

Song, Soohyun; Jung, Surim; Kwon, Mijung

doi:10.5483/bmbrep.2023-0025

Cited by 11 publications

(6 citation statements)

References 89 publications

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“…This in turn can enhance tumorigenic properties of cancer cells. Numerical chromosomal instability induced by centrosome amplification can also accelerate the onset and spread of carcinomas via the accumulation of genetic mutations ( 19 , 83 , 85 ). Hence, the genomic instability that drives the development of cancer is exacerbated by these anomalies, which hinders the proper segregation of chromosomes during cell division.…”

Section: Centrosomes and Their Associated Proteins In Breast Cancermentioning

confidence: 99%

Centrosomes and associated proteins in pathogenesis and treatment of breast cancer

Athwal,

Kochiyanil,

Bhat

et al. 2024

Front. Oncol.

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Breast cancer is the most prevalent malignancy among women worldwide. Despite significant advances in treatment, it remains one of the leading causes of female mortality. The inability to effectively treat advanced and/or treatment-resistant breast cancer demonstrates the need to develop novel treatment strategies and targeted therapies. Centrosomes and their associated proteins have been shown to play key roles in the pathogenesis of breast cancer and thus represent promising targets for drug and biomarker development. Centrosomes are fundamental cellular structures in the mammalian cell that are responsible for error-free execution of cell division. Centrosome amplification and aberrant expression of its associated proteins such as Polo-like kinases (PLKs), Aurora kinases (AURKs) and Cyclin-dependent kinases (CDKs) have been observed in various cancers, including breast cancer. These aberrations in breast cancer are thought to cause improper chromosomal segregation during mitosis, leading to chromosomal instability and uncontrolled cell division, allowing cancer cells to acquire new genetic changes that result in evasion of cell death and the promotion of tumor formation. Various chemical compounds developed against PLKs and AURKs have shown meaningful antitumorigenic effects in breast cancer cells in vitro and in vivo. The mechanism of action of these inhibitors is likely related to exacerbation of numerical genomic instability, such as aneuploidy or polyploidy. Furthermore, growing evidence demonstrates enhanced antitumorigenic effects when inhibitors specific to centrosome-associated proteins are used in combination with either radiation or chemotherapy drugs in breast cancer. This review focuses on the current knowledge regarding the roles of centrosome and centrosome-associated proteins in breast cancer pathogenesis and their utility as novel targets for breast cancer treatment.

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Section: Centrosomes and Their Associated Proteins In Breast Cancermentioning

confidence: 99%

Centrosomes and associated proteins in pathogenesis and treatment of breast cancer

Athwal,

Kochiyanil,

Bhat

et al. 2024

Front. Oncol.

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“…Numerical aberrations, most associated with centrosome amplification, can arise from overduplication, fragmentation, or tetraploidization. Irrespective of the mechanism, centrosome amplification is linked to numerous pathological diseases and is a hallmark of most cancers 6 . An increase in centrosome numbers is linked to defective mitosis and chromosome segregation defects that likely contribute to acquisition of chromosome abnormalities and genomic instability 4 .…”

Section: Introductionmentioning

confidence: 99%

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability

Chowdhury,

Wang,

Love

et al. 2024

Preprint

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Centrosomes play a fundamental role in nucleating and organizing microtubules in the cell and are vital for faithful chromosome segregation and maintenance of genomic stability. Loss of structural or functional integrity of centrosomes causes genomic instability and is a driver of oncogenesis. The lysine demethylase 4A (KDM4A) is an epigenetic ‘eraser’ of chromatin methyl marks, which we show also localizes to the centrosome with single molecule resolution. We additionally discovered KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis, and is required for centrosome integrity, a new functionality unlinked to altered expression of genes regulating centrosome number. We find rather, that KDM4A interacts with both mother and daughter centriolar proteins to localize to the centrosome in all stages of mitosis. Loss ofKDM4Aresults in supernumerary centrosomes and accrual of chromosome segregation errors including chromatin bridges and micronuclei, markers of genomic instability. In summary, these data highlight a novel role for an epigenetic ‘eraser’ regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome.

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“…Centrosomes are key to microtubule organization and cell division, with their dysfunction linked to diseases like cancer, where cells often have excess centrosomes that promote genomic instability and tumor growth [ 1 – 3 ]. For cancer cells with supernumerary centrosomes, clustering is crucial to achieve bipolar division and sustain their survival.…”

Section: Introductionmentioning

confidence: 99%

Nek2A prevents centrosome clustering and induces cell death in cancer cells via KIF2C interaction

Kalkan,

Ozcan,

Cicek

et al. 2024

Cell Death Dis

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Unlike normal cells, cancer cells frequently exhibit supernumerary centrosomes, leading to formation of multipolar spindles that can trigger cell death. Nevertheless, cancer cells with supernumerary centrosomes escape the deadly consequences of unequal segregation of genomic material by coalescing their centrosomes into two poles. This unique trait of cancer cells presents a promising target for cancer therapy, focusing on selectively attacking cells with supernumerary centrosomes. Nek2A is a kinase involved in mitotic regulation, including the centrosome cycle, where it phosphorylates linker proteins to separate centrosomes. In this study, we investigated if Nek2A also prevents clustering of supernumerary centrosomes, akin to its separation function. Reduction of Nek2A activity, achieved through knockout, silencing, or inhibition, promotes centrosome clustering, whereas its overexpression results in inhibition of clustering. Significantly, prevention of centrosome clustering induces cell death, but only in cancer cells with supernumerary centrosomes, both in vitro and in vivo. Notably, none of the known centrosomal (e.g., CNAP1, Rootletin, Gas2L1) or non-centrosomal (e.g., TRF1, HEC1) Nek2A targets were implicated in this machinery. Additionally, Nek2A operated via a pathway distinct from other proteins involved in centrosome clustering mechanisms, like HSET and NuMA. Through TurboID proximity labeling analysis, we identified novel proteins associated with the centrosome or microtubules, expanding the known interaction partners of Nek2A. KIF2C, in particular, emerged as a novel interactor, confirmed through coimmunoprecipitation and localization analysis. The silencing of KIF2C diminished the impact of Nek2A on centrosome clustering and rescued cell viability. Additionally, elevated Nek2A levels were indicative of better patient outcomes, specifically in those predicted to have excess centrosomes. Therefore, while Nek2A is a proposed target, its use must be specifically adapted to the broader cellular context, especially considering centrosome amplification. Discovering partners such as KIF2C offers fresh insights into cancer biology and new possibilities for targeted treatment.

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Expanding roles of centrosome abnormalities in cancers

Cited by 11 publications

References 89 publications

Centrosomes and associated proteins in pathogenesis and treatment of breast cancer

Centrosomes and associated proteins in pathogenesis and treatment of breast cancer

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability

Nek2A prevents centrosome clustering and induces cell death in cancer cells via KIF2C interaction

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