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

Naso, Francesco; Boi, Dalila; Ascanelli, Camilla; Pamfil, Georgiana; Lindon, Catherine; Paiardini, Alessandro; Guarguaglini, Giulia

doi:10.1038/s41388-021-01766-w

Cited by 37 publications

(35 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This genome-wide regulation of nuclear RNA processing events by NEK2 is similar to what recently reported for another oncogenic mitotic kinase, AURKA. Indeed, up-regulation of AURKA in cancer cells also promotes its translocation to the nucleus, where it regulates the activity of transcription and splicing factors, resulting in modulation of gene expression programs [ 54 ]. Thus, it is tempting to speculate that the upregulation of mitotic kinases, including NEK2 and AURKA, frequently observed in many cancer types results in the gain of a nuclear function that directly or indirectly modulates the transcriptome of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

Naro

Musso

Monache

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Triple-negative breast cancer (TNBC) is the most heterogeneous and malignant subtype of breast cancer (BC). TNBC is defined by the absence of expression of estrogen, progesterone and HER2 receptors and lacks efficacious targeted therapies. NEK2 is an oncogenic kinase that is significantly upregulated in TNBC, thereby representing a promising therapeutic target. NEK2 localizes in the nucleus and promotes oncogenic splice variants in different cancer cells. Notably, alternative splicing (AS) dysregulation has recently emerged as a featuring trait of TNBC that contributes to its aggressive phenotype. Methods To investigate whether NEK2 modulates TNBC transcriptome we performed RNA-sequencing analyses in a representative TNBC cell line (MDA-MB-231) and results were validated in multiple TNBC cell lines. Bioinformatics and functional analyses were carried out to elucidate the mechanism of splicing regulation by NEK2. Data from The Cancer Genome Atlas were mined to evaluate the potential of NEK2-sensitive exons as markers to identify the TNBC subtype and to assess their prognostic value. Results Transcriptome analysis revealed a widespread impact of NEK2 on the transcriptome of TNBC cells, with 1830 AS events that are susceptible to its expression. NEK2 regulates the inclusion of cassette exons in splice variants that discriminate TNBC from other BC and that correlate with poor prognosis, suggesting that this kinase contributes to the TNBC-specific splicing program. NEK2 elicits its effects by modulating the expression of the splicing factor RBFOX2, a well-known regulator of epithelial to mesenchymal transition (EMT). Accordingly, NEK2 splicing-regulated genes are enriched in functional terms related to cell adhesion and contractile cytoskeleton and NEK2 depletion in mesenchymal TNBC cells induces phenotypic and molecular traits typical of epithelial cells. Remarkably, depletion of select NEK2-sensitive splice-variants that are prognostic in TNBC patients is sufficient to interfere with TNBC cell morphology and motility, suggesting that NEK2 orchestrates a pro-mesenchymal splicing program that modulates migratory and invasive properties of TNBC cells. Conclusions Our study uncovers an extensive splicing program modulated by NEK2 involving splice variants that confer an invasive phenotype to TNBCs and that might represent, together with NEK2 itself, valuable therapeutic targets for this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

Naro

Musso

Monache

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…In addition, the integrated function of all the different sequence elements is not known and constitutes a fundamental research quest of a complete framework of AURKA transcriptional regulation. It is also important to note the recurring phenomenon in which transcription of AURKA is regulated by some factors that AURKA engages with in protein-protein interactions, such as p53 [86], HIF1 [87], EGFR [88], Myc and FOXM1 [7] (figure 1). This suggests the presence of uncharted regulatory feedback loops, the exploration of which may reveal integrative circuits that control critical cellular functions, in addition to being exploited for therapeutic purposes [89,90].…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

Cacioppo

Lindon

2022

Open Biol.

Self Cite

View full text Add to dashboard Cite

Aurora Kinase A (AURKA) is a positive regulator of mitosis with a strict cell cycle-dependent expression pattern. Recently, novel oncogenic roles of AURKA have been uncovered that are independent of the kinase activity and act within multiple signalling pathways, including cell proliferation, survival and cancer stem cell phenotypes. For this, cellular abundance of AURKA protein is per se crucial and must be tightly fine-tuned. Indeed, AURKA is found overexpressed in different cancers, typically as a result of gene amplification or enhanced transcription. It has however become clear that impaired processing, decay and translation of AURKA mRNA can also offer the basis for altered AURKA levels. Accordingly, the involvement of gene expression mechanisms controlling AURKA expression in human diseases is increasingly recognized and calls for much more research. Here, we explore and create an integrated view of the molecular processes regulating AURKA expression at the level of transcription, post-transcription and translation, intercalating discussion on how impaired regulation underlies disease. Given that targeting AURKA levels might affect more functions compared to inhibiting the kinase activity, deeper understanding of its gene expression may aid the design of alternative and therapeutically more successful ways of suppressing the AURKA oncogene.

show abstract

“…Aurora-A is a member of the Aurora family of serine/threonine kinases. Aurora-A can phosphorylate itself at Thr288 and binds to tubulin TPX2 to regulate mitosis by controlling centriole and spindle formation [25] . In addition, Aurora-A regulates NF-κB [ 26 , 27 ], Hippo [28] , PI3K/Akt/mTOR [29] and other molecular signalling pathways to affect tumour proliferation, invasion and metastasis [30] .…”

Section: Discussionmentioning

confidence: 99%

KIAA1529 regulates RAD51 expression to confer PARP inhibitors resistance in ovarian cancer

Qiao

Zhou

et al. 2022

Translational Oncology

View full text Add to dashboard Cite

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

Cited by 37 publications

References 101 publications

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

KIAA1529 regulates RAD51 expression to confer PARP inhibitors resistance in ovarian cancer

Contact Info

Product

Resources

About