Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer

Abstract

The Aurora-A kinase regulates cell division, by controlling centrosome biology and spindle assembly. Cancer cells often display elevated levels of the kinase, due to amplification of the gene locus, increased transcription or post-translational modifications. Several inhibitors of Aurora-A activity have been developed as anti-cancer agents and are under evaluation in clinical trials. Although the well-known mitotic roles of Aurora-A point at chromosomal instability, a hallmark of cancer, as a major link between Aurora-A overexpression and disease, recent evidence highlights the existence of non-mitotic functions of potential relevance. Here we focus on a nuclear-localised fraction of Aurora-A with oncogenic roles. Interestingly, this pool would identify not only non-mitotic, but also kinase-independent functions of the kinase. We review existing data in the literature and databases, examining potential links between Aurora-A stabilisation and localisation, and discuss them in the perspective of a more effective targeting of Aurora-A in cancer therapy.

Fig. 1. Meta-analysis of Aurora-A localisation.

Locations scored as ‘nuclear’, ‘cytoplasmic/membranous’ or ‘cytoplasmic/membranous and nuclear’ in the database (here we have removed the designation ‘membranous’ as misleading) are expressed as percentage of total Aurora-A-positive samples for each tumour type (n ≥ 4).

Fig. 2. Aurora-A functions in regulating transcription and stability of oncoproteins.

A Aurora-A can increase Myc expression directly, through promoter shift, in combination with hnRNP K; a potential indirect effect, also mediated by hnRNP K, may also represent an indirect Aurora-A contribution to elevated Myc levels. The right panel schematises the transcriptional effect of Aurora-A on FOXM1 gene expression. The dashed arrow indicates potential direct binding of an Aurora-A/FOXM1 complex to the FOXM1 promoter. In turn, Myc and FOXM1 can upregulate AURKA gene expression. B The N-Myc protein sequence is schematically represented on top; myc boxes and DNA-binding domains are indicated, as well as the binding regions to Aurora-A and FBXW7. FBXW7 recognises and ubiquitinates N-Myc, inducing proteasome-mediated degradation (lower left panel). Aurora-A binding protects N-Myc from FBXW7-mediated degradation (lower right panel). Created with BioRender.com.

Fig. 3. Overview of cancer-associated Aurora-A mutations and their functional relevance.

The mutation profile of Aurora-A in cancer is shown, together with the potential partners whose physical or functional interaction can be influenced by the mutations. Data from COSMIC v92 release (August 2020) lists a total of 455 unique samples with mutations. Created with BioRender.com.

Fig. 4. Targeting of interphase and mitotic functions of Aurora-A.

Aurora-A functions in an interphase (left) or mitotic (right) cell are schematised, with indication of their dependence on specifically localised Aurora-A pools or on kinase activity. On this basis, we propose that different classes of Aurora-A inhibitors (schematised on the right and indicated by symbols within the cell) can differently affect different Aurora-A functions. Created with BioRender.com.