A centrosomal route for cancer genome instability

Despite the widespread occurrence of aneuploidy in cancer cells, the molecular causes for chromosomal instability are not well established. Cyclin B2 is now shown to control a pathway — involving the centrosomal kinases aurora A and Plk1 and the tumour suppressor p53 — the alteration of which causes defective centrosome separation, aneuploidy and tumour development.

A frequent question in cancer biology is whether tumour-associated overexpression of proteins is just a consequence of cell transformation or whether it indicates a causal role for the protein. This question is especially difficult to address in the case of cell cycle regulators, given the general increase in cell proliferation rates observed in tumour cells. Genomic studies have suggested the presence of an expression signature in which the overexpression of about 70 genes is associated with chromosomal instability (CIN) in cancer1. This signature is enriched in regulators of the cellular machineries that control centrosome maturation and spindle dynamics, as well as the orderly segregation of chromosomes in every cell cycle (Fig. 1). Yet the mechanistic basis for the role of these regulators in tumour development is largely unknown. In this issue, Nam and van Deursen2 find that two members of the CIN signature, cyclin B1 and cyclin B2, are important for the fidelity of chromosome segregation and centrosome separation, and demonstrate the consequences of their overexpression for tumour development.

Figure 1: A general view of centrosomal and mitotic regulators involved in chromosomal instability.

Overexpression of some of these molecules induces tumour development in mouse models. Reduced levels of the corresponding proteins (in most cases using heterozygous mutant mice) also results in increased tumour development in mice. Blue molecules are kinases and orange are kinase activators. Other regulators are shown in purple. AurkA and AurkB: aurora A and B.

Division of cells requires an accurate duplication of the genome during the DNA synthesis phase and proper segregation of the two sets of chromosomes to each of the daughter cells during mitosis. Defects in the cell cycle machinery are commonly linked to cancer, either by promoting unscheduled proliferation, or by allowing the introduction of genomic abnormalities in the daughter cells3. The widespread presence of abnormal chromosome number in tumours4 (a state known as aneuploidy) has inspired the hunt for new molecules that cause this defect in cancer cells when altered. Initial efforts discarded a general role for somatic mutations in mitotic genes, perhaps because of the essential role of many of these proteins in vivo5. However, multiple mitotic regulators display aberrant levels of mRNA or protein, and it is now well accepted that both increases and decreases in the expression of mitotic genes can induce CIN by altering the normal mechanisms that protect cells from aberrant chromosome segregation4,6. In the past few years, this has been elegantly demonstrated using loss- and gain-of-function mouse models of mitotic regulators (Fig. 1). The pioneering work on Mad2, a component of the spindle assembly checkpoint (SAC) that monitors proper microtubule–chromosome attachments, is a remarkable example6,7. In the presence of misaligned chromosomes, Mad2 inhibits the activity of the ubiquitin ligase APC/C (the anaphase-promoting complex), which, with its cofactor Cdc20, targets cyclin B1 and securin for degradation. Following complete bipolar attachment of chromosomes, the SAC is satisfied, resulting in the activation of APC/C–Cdc20. Rapid ubiquitin-dependent proteolysis of cyclin B1 and securin leads to inhibition of cyclin-dependent kinase 1 (Cdk1) and activation of separase, a protease that cleaves cohesins, thus resulting in sister chromatid separation and mitotic exit8. Multiple regulators of this process, including SAC inducers or effectors (aurora B, Mps1 or Mad2) as well as Cdc20, securin or separase are also part of the CIN signature (Fig. 1). Altering the expression levels of Mad2 in mouse models results in the formation of CIN tumours7 that frequently relapse9, which is in agreement with the poor prognosis of CIN tumours in humans. Similar data suggest that either downregulation or overexpression of other mitotic regulators such as separase10,11 may also favour tumour development (Fig. 1).

B-type cyclins are obligatory activators of Cdk1, a kinase that is also overexpressed as part of the CIN signature of cancer cells1. Cdk1 is a conserved regulator of the cell division cycle, and is required for multiple processes during mitotic entry including centrosome dynamics, chromosome condensation, Golgi disassembly and nuclear envelope breakdown. During the early stages of mitosis, Cdk1–cyclin-B complexes are also able to inhibit separase, both by phosphorylation and the formation of ternary complexes, thus preventing precocious mitotic exit12. Most of these functions have been frequently attributed to Cdk1–cyclin-B1, perhaps motivated by the fact that cyclin B1, similarly to Cdk1, is essential for mitotic entry in mammals, whereas cyclin-B2-null cells or mice do not display major phenotypic defects3,13. Whether cyclin B2 displays separate, specific functions has remained largely unknown.

Nam and van Deursen now show that overexpression of either cyclin B1 or cyclin B2 can induce chromosome mis-segregation and tumour formation in mice2. By performing an elegant mechanistic dissection, Nam and van Deursen find that these two cyclins function in different pathways. In agreement with the known role for Cdk1 in the inhibition of separase, cyclin B1 overexpression interferes with the timely activation of separase following chromosome bi-orientation. This results in anaphase bridges or anaphase failure (Fig. 2) in the presence of low levels of separase activity, as monitored with a novel biosensor, even in conditions in which the SAC has already been satisfied2. Unexpectedly, overexpression of cyclin B2 results in a different phenotype characterized by the presence of lagging chromosomes and defects in spindle geometry. Using a variety of gain- and loss-of-function models, the authors demonstrate that cyclin B2 (which is likely to be activating Cdk1) initiates centrosome separation in G2 by triggering the activation of the centrosomal kinase aurora A. How precisely cyclin B2 regulates aurora A activation is not yet established. Aurora A is known to be required for the activation of Polo-like kinase 1 (Plk1), which controls centrosome separation by inducing the Nek2a-dependent phosphorylation of c-Nap1 and the release of this factor from the centrioles14. C-Nap1 is a core centrosomal protein required for centriole–centriole cohesion during interphase. Activation of cyclin B2 therefore triggers a pathway that removes c-Nap1 from centrioles, resulting in centrosome separation. Interestingly, aurora A, Nek2 and c-Nap1 are all members of the CIN signature (Fig. 1), and Plk1 overexpression also correlates with CIN and poor prognosis in multiple tumour types5.

Figure 2: Cellular consequences of cyclin B2 and B1 overexpression in the centrosomal pathway and the control of sister chromatid separation.

(a) Cyclin B2 triggers the activation of Plk1 in an aurora-A-dependent manner, leading to premature centrosome separation, spindle geometry defects and lagging chromosomes (outlined in red) during mitosis. This pathway may be limited by the repression of aurora A and/or Plk1 in a p53-dependent manner. (b) Overexpression of cyclin B1, on the other hand, impairs the proper activation of separase, preventing cohesion cleavage and sister chromatid segregation, thus generating chromosomal bridges (outlined in red). Deregulation of these two processes leads to the generation of aneuploid cells, and may participate in tumour development.

Whereas lack of cyclin B2 results in un-separated centrosomes in a variety of cell types, Nam and van Deursen report the surprising observation that cyclin B2 deficiency has no effect in p53-null cells. p53 is a major tumour suppressor that can transcriptionally repress aurora A (ref. 15). In the absence of p53, aurora A is induced and the requirement for cyclin B2 in centrosome separation is lost. In fact, the authors find that p53-null cells also display premature centrosome separation and accumulate lagging chromosomes2, suggesting that cyclin B2 overexpression and p53 loss are two redundant pathways that control aurora-A-dependent initiation of the centrosome separation pathway. Whether these two pathways are mutually exclusive in human tumours remains to be determined. Overexpression of cyclin B1 or B2 in mice results in increased susceptibility to multiple tumours2, with lung tumour as the most prevalent disease in agreement with other CIN models6. Overexpression of these two cyclins also cooperates with other oncogenes or carcinogenic treatments, and these tumours are not addicted to the continuous presence of the transgenes2, suggesting a role for chromosomal instability in generating a proper genomic scenario for the accumulation of tumour mutations during the initial phases of tumour development6,7.

What is the relevance of centrosomal or mitotic functional aberrations in human cancer? This is not well appreciated at the moment, owing to the lack of frequent mutations in the corresponding genes and the technical difficulties of monitoring small changes in expression levels or functional defects in centrosome or chromosome segregation in patients. However, the overexpression of mitotic regulators belonging to the CIN signature is found in a wide variety of tumour types1,5. In addition, loss of p53 is one of the most common genetic events in human cancer. We have previously introduced the concept of oncogene-induced mitotic stress16 to highlight the fact that many oncogenic events in the cell, including loss of the tumour suppressor p53, results in altered levels of several mitotic regulators, such as Mad2 or aurora A. These events are likely to cause parallel centrosome and chromosome segregation errors at multiple levels. How tumour cells deal with the undesired defects of these alterations is an important question. For instance, cyclin B1 and separase are both part of the CIN signature. As the oncogenic effect of cyclin B1 overexpression is now proposed to be mediated by its ability to inhibit separase2, the concomitant overexpression of both proteins could compensate each other. A similar prediction can be made with the overexpression of c-Nap1 in the presence of cyclin B1, aurora A or Nek2 overexpression. It is likely that clones with the more optimal combination of these factors are selected during tumour development. It is not at all clear what is the best therapeutic approach to correct chromosome instability in cancer, especially given that tumours are not addicted to these alterations2,7. Yet, inducing further chromosomal instability to treat these tumours stands out as an attractive possibility.


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Correspondence to Marcos Malumbres.

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de Cárcer, G., Malumbres, M. A centrosomal route for cancer genome instability. Nat Cell Biol 16, 504–506 (2014). https://doi.org/10.1038/ncb2978

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