Research progress on the relationship between AURKA and tumorigenesis: the neglected nuclear function of AURKA

Abstract

AURKA is a threonine or serine kinase that needs to be activated by TPX2, Bora and other factors. AURKA is located on chromosome 20 and is amplified or overexpressed in many human cancers, such as breast cancer. AURKA regulates some basic cellular processes, and this regulation is realized via the phosphorylation of downstream substrates. AURKA can function in either the cytoplasm or the nucleus. It can promote the transcription and expression of oncogenes together with other transcription factors in the nucleus, including FoxM1, C-Myc, and NF-κB. In addition, it also sustains carcinogenic signaling, such as N-Myc and Wnt signaling. This article will focus on the role of AURKA in the nucleus and its carcinogenic characteristics that are independent of its kinase activity to provide a theoretical explanation for mechanisms of resistance to kinase inhibitors and a reference for future research on targeted inhibitors.

KEY MESSAGES

• AURKA plays an important role in the control of the proliferation, invasion, cell cycle regulation and self-renewal of cancer stem cells.

• Small molecule kinase inhibitors targeting AURKA have been developed, but the overall response rate of patients in clinical trials is not ideal, prompting us to pay attention to the non-kinase activity of AURKA.

• This review focuses on the nuclear function of AURKA and its oncogenic properties independent of kinase activity, demonstrating that the nuclear substrate of AURKA and the remote allosteric site of the kinase may be targets of anticancer therapy.

Keywords:

• AURKA
• transcription
• inhibitor resistance
• nuclear function

1. Introduction

AURKA is a threonine or serine kinase. Researchers first found a lineal homolog of AURKA, a protein called Ipl1, in germinating yeast [1]. Since then, Ipl1 has been identified in Xenopus laevis, Drosophila melanogaster and Caenorhabditis elegans, and has been identified to regulate centrosome stability and maintain mitotic spindle formation [2–4]. Studies further found that three orthologous proteins of Ipl1, namely, the Aurora kinases AURKA, AURKB and AURKC, exist in mammals. Overexpression of these proteins has been identified in several cancers; this phenotype is closely related to amplification of the AURKA gene on chromosome 20q13 [5], and AURKA overexpression is found in skin, breast, ovarian, colon and other tumors [6–11].

Given that AURKA has been found to be aberrantly expressed in a variety of tumors since its discovery, it was identified as an oncogene [12]. High levels of AURKA are associated with malignant tumor proliferation [13], invasion and metastasis [14], splicing disorders [15], epithelial-mesenchymal transformation [16], radioresistance [17], chemotherapy resistance [18] and immune escape [19]. Therefore, small molecule kinase inhibitors targeting AURKA have been successively developed. Although they have shown certain effects in preclinical studies [20, 21], their efficacy in clinical trials is poor [22]. The reason for this is that the understanding of AURKA itself is not comprehensive, and simply blocking AURKA kinase activity is usually not enough to achieve maximum therapeutic efficacy [23, 24]. Many studies have focused on the way in which nuclear AURKA, rather than cytoplasmic AURKA, enhances the carcinogenic characteristics of tumors by activating Myc [19, 25], HIF1 [26], Ras [27], and so on.

Here, we mainly focus on research related to the nuclear function of AURKA, starting with resistance to targeted inhibitors of AURKA kinase, review the research on the carcinogenic effects of AURKA that are independent of its kinase activity, and explain the relationship between AURKA spatial distribution and its carcinogenic properties, with the aim of improving the understanding of the unique characteristics of AURKA in relation to cancer. In particular, we hope to provide a deeper understanding of the unique dynamics, which will be a valuable reference for future patient classification for targeted therapy.

2. High nuclear AURKA expression is associated with a poor prognosis in cancer patients

One study revealed that AURKA staining in malignant tumor tissue is mainly located in the nucleus, and this staining pattern could predict adverse clinical prognosis of tumor patients [28–30]. The expression of AURKA messenger ribonucleic acid (mRNA) can predict clinical prognosis and is highly positively correlated with advanced tumor stage in hepatocellular carcinoma patients [31]. Immunohistochemistry can be used to label specific antigens by assessing the distribution of bound antibodies in tissues. Immunohistochemistry analysis showed that AURKA is expressed in the nucleus and cytoplasm, and this expression pattern was associated with high tumor grade, poor prognosis of patients and abnormal p53. The cytoplasm of ovarian cancer cells is the main location of phosphorylated AURKA. Ovarian cancer cells show no nuclear overexpression of AURKA protein, and instead, the protein is mostly found in the cytoplasm. Phosphorylated AURKA does not carry a nuclear localization signal at Thr288. The regulation of nuclear AURKA requires other mechanisms. When the protein acts in the cytoplasm, Aurora-A phosphorylation at Thr288 has a functional role [32]. This phenomenon explains the correlation between aggressive clinical features and the presence of Aurora-A in the cytoplasm and phosphorylated Aurora-A. In Masaaki Tatsuka’s study, head and neck cancer cell nuclei showed overexpression of AURKA, suggesting that nuclear proteins can be targeted by AURKA; this finding is significant for understanding the relationship between the localization of AURKA in the nucleus and carcinogenic transformation [27]. Lee et al. [33] analyzed relative phosphorylated AURKA and total nuclear and cytoplasmic AURKA levels in HPV-negative head and neck squamous cell carcinoma (HNSCC) patients and found that a decreased survival rate was related to the phosphorylation and nuclear overexpression of AURKA in p16-negative HNSCC patients, but there was no correlation of OS with phosphorylated AURKA or cytoplasmic AURKA levels. Nuclear AURKA also plays a carcinogenic role in oral squamous cell carcinoma, and the survival of patients is not affected by the high nuclear expression of AURKA in tumor tissue [34].

3. The AURKA core: functional diversification

Typical kinase domains of human Aurora-A contain residues 133 to 383 [35]. Aurora-A is a protein with 403 amino acids. Researchers assessed the 1–333 and 1–383 amino acid sequences of AURKA and found that the nuclear localization signal (NLS) of AURKA determines the nuclear localization of AURKA. The NLS exists within amino acids 333–383 of the sequence. Furthermore, the nuclear output signal (NES) exists within amino acids 1–333, and the presence of an NLS or NES signal determines the subcellular localization of AURKA (in the nucleus or cytoplasm) [25]. This is consistent with Masaaki Tatsuka’s finding that Aurora-A fuses with the nuclear output signal, thereby disrupting its nuclear localization [27]. Moreover, overexpression of K/H-Ras (G12V mutant) resulted in a significant increase in the AURKA nuclear/cytoplasmic ratio in mouse embryonic fibroblasts [25], while the K-Ras G12V mutant was also shown to be able to increase Aurora-A expression in ovarian, pancreatic and lung cancer cells [36–38]. Recent studies have shown that the AURKA nuclear/cytoplasmic ratio is increased in hTERT RPE-1 cells during the G2 phase of mitosis [39]. However, AURKA overexpression is not sufficient to increase AURKA nuclear localization, while LMB, epoxomicin and APC/C inhibitor treatment lead to AURKA nuclear enrichment [39]. TPX2 and AURKA have been shown to be coexpressed in pancreatic cancer and breast cancer [37, 39]. Interestingly, compared with AURKA-overexpressing cells, AURKA/TPX2-overexpressing cells exhibited AURKA nuclear enrichment, which was more evident after proteasome inhibition, while inhibition of AURKA kinase activity with kinase inhibitors did not affect AURKA nuclear localization [39]. These results indicate that AURKA nuclear localization is regulated by the cell cycle, nuclear export, proteasome and TPX2, but AURKA kinase activity has no effect on its nuclear localization [39]. This largely explains the resistance to and off-target effects of kinase inhibitor monotherapy in AURKA-overexpressing cancers. Therefore, how does the nuclear localization signal mediate the oncogenic properties of AURKA?

3.1. AURKA is involved in regulating gene transcription

In addition to the physiological role of AURKA in cell division, its nonmitogenic role in cancer cells has received much attention in recent years [35, 40]. AURKA exerts key functions in the nucleus as a transcription factor and transcription activator, roles by which it regulates gene transcription (Figure 1). AURKA localization in the nucleus was variable in the study of Zhang et al. Fluorescence resonance energy transfer (FRET) technology exists between AURKA molecules and can enhance the proliferation of breast cancer stem cells and activate Myc transcription, which is supported by the direct action of the nuclear ribonucleoprotein hnRNPK and AURKA. However, this new function of AURKA is only applicable in the nucleus and cannot be performed by inactive AURKA [21]. Moreover, the spatiotemporal location of AURKA outside mitosis is closely related to its carcinogenicity, and there is no correlation between the mitotic action of kinase and the transcriptional activation of AURKA on Myc, which has also been proven in the study [25]. Myc can bind to the AURKA promoter and activate its transcription, indicating the existence of a positive feedback loop [41]. Masaaki Tatsuka et al. proved that AURKA accumulated in the nucleus, as the downstream signal of Src-Ras-Raf signaling, transformed the Ras carcinogenic signal of cancer cells in the nucleus in head and neck cancer, supporting a functional role of AURKA in the processing of catalytic nuclear substrates [27]. Transcription coactivators can also serve as oncogenes related to AURKA. Forkhead box subclass M1 (FOXM1) recruits nuclear AURKA. As FOXM1 is a cofactor, the activation of FOXM1 target genes mainly depends on a kinase-independent mechanism. FOXM1 and AURKA participate in the positive feedback circuit to enhance the BCSC phenotype of breast cancer [42]. In invasive breast cancer patients, high expression of nuclear NF-κB mediated by amplification of AURKA can be detected and induces radiation resistance [43, 44]. Through phosphorylation, IκBα activates NF-κB in the nucleus, which decreases the apoptosis-inducing effects of radiotherapy on cancer cells. In upper gastrointestinal adenocarcinoma, overexpression of AURKA can induce its nuclear translocation through phosphorylation of STAT3, directly activate STAT3 via transcription, and activate the expression of its target genes after the two interact [45]. Nuclear AURKA has recently been found to bind to HIF1A/B and promote the transactivation of hypoxia response genes, thereby driving early breast cancer spread and metastasis, independent of kinase activity [26]. In addition, nuclear/noncytoplasmic AURKA promotes PD-L1 expression in breast cancer cells through a Myc-dependent pathway, contributing to the immune escape of TNBC, suggesting that nuclear AURKA can regulate the immune response of tumors [19]. Transcription factors are located in the nucleus and need a specific nuclear AURKA to activate them. STAT3 and NF-κB are the same as the transcription factor Myc. Thus, it is easy to infer that nuclear AURKA can activate multiple transcription factors at the same time. Transcription factors such as GSK3B and CTNNB1 should be studied to help clarify their activation sequence [40].

Figure 1. AURKA is involved in the regulation of oncogene transcription.

AURKA functions as a transcription factor and transcriptional coactivator in the nucleus, participates in the regulatory mechanisms of cancer cells, and generates carcinogenic signals. AURKA in the nucleus affects biological processes of breast cancer stem cells through a kinase-independent mechanism. This review has focused on clarifying the relationship between AURKA in the nucleus and its downstream transcriptional network, as well as the function of AURKA in the nucleus from a new perspective, hoping to provide a theoretical foundation for the identification of chemotherapeutic drugs targeting AURKA.

3.2. AURKA promotes and sustains oncogenic signaling

Abnormal Wnt signaling may underlie many diseases in humans. AURKA is a key protein affecting the stability of Wnt pathway signaling (Figure 2). FoxM1 is a key molecule related to cellular accumulation of beta-catenin. In the Wnt signaling pathway, FoxM1 and beta-catenin combine in the nucleus with TCF4 in the promoter region of the Wnt gene to jointly regulate the stemness of GICs. However, FOXM1 decreases the overall expression of beta-catenin [46]. Other studies have shown that overactivated AURKA in glioma-initiating cells (GICs) can bind AXIN (a multidomain scaffold protein that aids the assembly of the β-catenin destructive complex [47]) to suppress β-catenin complex formation, which reduces the phosphorylation of β-catenin and its stability in the nucleus. Subsequently, the destructive complex activates Wnt signaling in the nucleus and promotes GIC self-renewal. This effect of AURKA is due to its protein expression, not its kinase activity [48]. The mechanism by which AURKA affects oncogenic complexes through protein binding to inhibit oncoprotein degradation is not limited to Wnt signaling. Fbxw7 is a ubiquitin ligase that induces N-Myc degradation, and AURKA can fully bind to Fbxw7, thereby inhibiting the degradation of the oncogenic signaling protein N-Myc. Interestingly, AURKA kinase activity is not essential for N-Myc stabilization, indicating that kinase activity is not the only important carcinogenic characteristic of AURKA [49,50]. MYCN and AURKA are expressed at high levels in neurocytomas, medulloblastomas, acute myeloid leukemia, glioblastomas, astrocytoma, and prostate cancers, suggesting that the stabilization effect of Aurora-A on N-Myc may be present across solid tumors.

Figure 2. AURKA promotes the stability of carcinogenic signals.

3.3. AURKA promotes the aberrant splicing of RNAs associated with cancer

Aberrant RNA splicing can generate different gene subtypes, which can induce tumor invasion and metastasis [51], epithelial-mesenchymal transition [52], angiogenesis [53], and anticancer resistance [54]. Nuclear AURKA may promote tumor progression by regulating RNA splicing [15,55]. RNA splicing requires splicing factors such as heterogeneous nuclear ribonucleoprotein (HNRNP) proteins [56], serin -and arginine-rich (SR) proteins [57], and RNA binding motif (RBM) proteins [58], which bind to regulatory elements in pre-mRNA to regulate its maturation. Previous studies have shown that RBM4 acts as a tumor suppressor by specifically controlling cancer-associated splicing [59]. Recent studies have found that nuclear translocation of AURKA is a prerequisite for aberrant RNA splicing. Nuclear AURKA triggers the splicing of RBM4 from the complete isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner, reversing the inhibition of SRSF1-mTORC1 activity by RBM4-FL and promoting tumor progression [15]. The regulation of RBM4 splicing by nuclear AURKA is mainly dependent on the m6A reader YTHDC1, which inhibits the binding of YTHDC1 to SRSF3, thereby blocking the production of RBM4-FL induced by the m6A-YTHDC1-SRSF3 complex. In turn, it promotes the binding of hnRNPK and YTHDC1, thereby mediating m6A-YTHDC1-hnRNPK-dependent exon skipping leading to RBM4-S production [15]. Further studies found that targeting AURKA kinase activity did not affect RBM4 splicing from RBM4-FL to RBM4-S, while the AURKA nuclear translocation inhibitor PHA-680632 and the E3 ligase inhibitor NJ-26854165 reversed RBM4-FL splicing to inhibit lung cancer growth [15]. In breast cancer, the AURKA-YBX1/hnRNPK complex has been shown to be associated with a poor prognosis. AURKA binds to the splicing factor hnRNPK to promote RBM4 exon skipping, leading to RBM4-S production. Interaction with YBX1 promotes GOLGA4 exon inclusion to induce GOLGA4-FL production, and its aberrant splicing of RBM4 and GOLGA4 is blocked by nuclear translocation inhibitors [55] (Figure 3).

Figure 3. AURKA promotes aberrant splicing of RNAs associated with cancer.

These data suggest that AURKA forms complexes with cofactors or oncogenic transcription factors to directly regulate RNA splicing but do not explain whether AURKA has a regulatory effect in RNA splicing. Therefore, targeting the AURKA complex can be used as a potential therapeutic means to inhibit aberrant RNA splicing and improve the prognosis of patients.

4. AURKA polymorphisms

The identification of single nucleotide polymorphisms related to key functions and the expression of genes will improve the understanding of the pathogenesis of tumors [60]. Two single nucleotide polymorphisms of human Aurora-A (A < 91T and A < 169G) produce four isoforms: F31/V57, I31/V57, F31/I57 and I31/I57 [61, 62]. Makoto T et al. found that different subtypes of AURKA have functional differences in esophageal epithelial cells. F31/I57 and I31/I57 exist not only in the nucleus but also in the cytoplasm but are only found in the cell. The kinase activity of the Aurora-A subtypes F31/V57 and I31/V57 was notably higher than that of F31/I57, but the activity of I31/I57 was the lowest, and I31/I57 phosphorylation was higher than F31/I57 phosphorylation, while I31/I57 lacked activity. These results show that the 57th amino acid residue is necessary for kinase activity [63]. Therefore, at the subcellular level, there are obvious differences in the kinase activity of the four types of proteins. On the one hand, the activity of protein kinases in tumor patients affects the curative effects in tumor patients. In addition, subcellular localization impacts the effect of inhibitors. Aurora-A gene polymorphisms should be considered in the treatment of this type of tumor and in subsequent clinical trials. Aurora-A protein kinase (Aurora-A) plays key functions in the expansion of tumors. However, one study revealed that the lower the Aurora-A kinase activity was, the greater the risk of cancer. To determine how other Aurora-A subtypes cause tumors, further research is needed. Genetic testing for Aurora-A polymorphisms and Aurora-A kinase activity will be helpful for identifying high-risk patients. Relevant results will enable regular examination of and early detection of cancer in patients at high risk of tumors [63].

5. Targeting AURKA

Due to the multiple functions that AURKA exhibits as a kinase during cancer cell mitosis, researchers have made great efforts to develop AURKA inhibitors for cancer therapy. Many inhibitors have been developed, some of which have entered clinical trial [23, 64–93] (Supplementary Information). However, AURKA inhibitors are essentially small ATP analogs that target a highly homologous ATP-binding site (active site) on the kinase, which is highly conserved among kinase families, and targeting the ATP-binding site of the kinase can lead to poor selectivity and possible side effects in patients. In addition, kinase active site mutations are prone to lead to the emergence of drug resistance [94]. To overcome inhibitor drug resistance, researchers have studied and designed type IV inhibitors that have an altered binding site to avoid activating the kinase and instead interact with its distal allosteric site [95, 96]. The data thus far show that interaction with the distant allosteric point of the kinase can effectively inhibit cell mitosis and reduce drug resistance (Table 1). In addition, another way to circumvent drug resistance is to study inhibitors that can effectively stabilize the inactive conformation of AURKA. Burgess et al. identified the shark heavy chain antitrope monoclonal antibody vNAR. The antibody was used to develop a new allosteric inhibitor that can compete with TPX2. All these drugs bind to the corresponding site on SUPKA, which can change the α subunit. The C-helix is twisted, and inhibitor binding can destroy the lysine-glutamate bridge (Table 1) [97]. However, AURKA allosteric inhibitors (Table 1) need to be further improved and have not yet entered clinical trials. Recently, researchers have explored potential AURKA kinase inhibitors based on computer-aided drug design. The MK8745 analog, lead compound 85 (NCI14040), SPB01812, JFD02217, SP01027 and KM00965 were identified as potential effective AURKA kinase inhibitors by 3D QSAR, MD simulation, molecular docking and virtual screening [98–100]. The search for AURKA kinase inhibitors continues, 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H)-one derivatives [101] and novel pyrazole analogs [102] were found to bind AURKA. These compounds have the potential to inhibit AURKA kinase activity. In addition, a salicylic aldehyde-modified analog of PF-06447475 binds to AURKA in a covalent and noncovalent manner and inhibits AURKA kinase activity [103].

Table 1. Allosteric inhibition of AURKA.

Company names (DrugBank ID)	Structures	Target	Mechanism of action	Cell-based potency (IC50/EC50)	Animal models	Ref
AurkinA		AURKA	AurkinA interacts with the rabies pocket (‘Y- pocket’) of AURKA, which houses the TPX2-specific Tyr-Ser-Tyr site, blocking the AURKA-TPX2 interaction and inducing conformational changes in AURKA, which inhibits AURKA activity inside and outside the cell.	AurkinA causes AURKA mislocalization and inhibits AURKA kinase activity in HeLa cells with EC50 of 135 µM.	/	[109]
vNAR-D01		AURKA (IC50 6.76 µM)	Interaction with TPX2 prevents binding with the catalytic domain of AURKA kinase, and binding of vNAR-D01 stabilizes the inactive confirmation of AURKA.	/	/	[97]
Felodipine (DB01023)		AURKA (IC50 20 µM)	Felodipine effectively inhibits the phosphorylation of histone H3 by Aurora-A in a dose-dependent manner, with minimal influence on the homolog Aurora-B.	The IC50 values for five cell types (HeLa S3, HEK293T, MCF7, HCT116, and C6) for the Aurora-A and Aurora-B kinases were between 6 and 12 μM.	In a C6 xenograft tumor Model, administration of felodipine, 5 mg/kg/day for 4 weeks significantly reduced the rate of rumen collapse in mice.	[110]
Tripoli A		AURKA (IC50 1.5 μM)	Tripoli A can stabilize or promote switching between different inactive conformations of Aurora A kinases by affecting sites such as the deep back pocket or DFG domain present in the FG-out conformation.	/	/	[111]
Lewis’ patent		AURKA (IC50 2.7 μM)	ATP noncompetitive inhibitor that inhibits function and TPX2 competition.	/	/	[112]
		AURKA	/	/	/
		AURKA	/	/	/
		AURKA (IC50 19.3 μM)	/	/	/
Conti’s patent		AURKA	Some of the above molecules are interact with several or single residues in the TPX2 joint region in Aurora A.	/	/	[113]
		AURKA	/	/	/

However, AURKA kinase inhibitors do not address any kinase activity-independent effects of nuclear AURKA, which may explain the poor clinical outcomes of kinase inhibitor therapy. In view of the regulation of oncogenes by nuclear AURKA at the transcriptional and protein levels, AURKA combined with other targeted therapies may have synergistic effects. AKI6038, an AURKA kinase inhibitor, combined with thiostrepton, a FOXM1 inhibitor, can effectively inhibit AURKA activity and the AURKA/FOXM1 positive feedback loop, and synergistically inhibit the tumorigenesis of breast cancer stem cells [42]. Through screening the drug library, researchers found that the Aurora kinase inhibitor PHA-680632 and the E3 ligase inhibitor JNJ-26854165 could promote AURKA accumulation in the cytoplasm of A549 and NCI-H460 cells and prevent AURKA nuclear translocation [15]. In addition, proteolytic targeting chimeras (PROTACs) are bifunctional molecules consisting of ligands that bind to E3 ubiquitin ligases, appropriate adaptors and the parent ligand of the target protein (POI). PROTACs induce binding of the POI to E3 ubiquitin ligases and stimulate POI ubiquitination for proteasomal degradation [104]. The PROTAC utilizing the AURKA kinase inhibitor alisertib was recently found to rapidly and specifically degrade the AURKA protein in cells and avoid mitotic arrest, instead arresting cells in the S phase of the cell cycle, which is different from the mitotic arrest observed with alisertib-mediated inhibition [105]. Mk-5108-based PROTACs degrades AURKA in a proteasome - and E3 ligase-dependent manner [106]. PROTAs induces sequential degradation of AURKA in AML stem cells, CRBN-based dAurA383 preferentially degrades mitotic AURKA, and CIAP-based dAurA450 degrades interphase AURKA, indicating that it is a promising spatiotemporal drug delivery strategy [107]. This strategy has the advantage of inhibiting both the catalytic and noncatalytic functions of AURKA [107, 108]. Therefore, targeting nuclear AURKA and inhibiting its nuclear translocation may help to solve kinase inhibitor resistance and make better use of AURKA as a target for antitumor therapy.

6. Discussion and outlook

AURKA is a signaling protein closely related to cell proliferation, invasion, survival and cell stage. AURKA is related to drug resistance [114, 115], radiotherapy resistance [43, 116–118] and other functions. High AURKA expression in cells is a common phenomenon in cancer, and protein kinase inhibitors targeting AURKA have been developed. However, increasing evidence shows that the clinical applications of AURKA kinase inhibitors are limited. Many recently developed inhibitors have not been successfully transitioned into clinical use due to drug resistance or off-target effects when they are applied as monotherapy and the toxic side effects of combination drugs. Here, we reviewed recent studies on the oncogenic functions of AURKA independent of its kinase activity and revealed key factors related to AURKA kinase inhibitor resistance. We believe that identifying the unique functions of specific kinases will enable new strategies to inactivate kinases through gene knockdown, gene knock-in and other means, which can then be compared with inhibitors. Such studies can be used to determine whether inhibitors or proteins can better target the kinase. The above problems must be overcome before AURKA can be employed as a target of tumor therapy. At present, there are still certain risks in the clinical application of AURKA inhibitors [119].

AURKA non-kinase functions are often overlooked. On the one hand, AURKA can cause changes in cell function by interacting with oncoproteins such as MYCN to form protein complexes. In this case, small molecule inhibitors cannot directly target the protein because they do not have suitable binding sites. The development of allosteric inhibitors can overcome this problem; such inhibitors can be redirected to bind with the remote allosteric site of the kinase and affect stability [120]. On the other hand, the non-kinase functions of AURKA are in part related to its nuclear localization, which is essential for its regulation of oncogene (C-Myc, FOXM1, NF-κB, STAT3) transcription and stabilization of oncogenic signals (Wnt, N-Myc). Therefore, it is necessary to focus on the subcellular localization of AURKA in future studies. Most previous studies have focused on the series of reactions caused by AURKA substrate phosphorylation, but this phosphorylation process is mostly carried out in the cytoplasm. Studies have shown that extremely high levels of nuclear AURKA are related to its biological function in cancer, and introducing relevant substrates into the nucleus may be a novel anticancer therapeutic strategy.

Authors’ contributions

The authors’ contributions to this review are as follows: Study conception: WL and JW; manuscript draft preparation: MC and JW; data collection, critical review, commentary, revision, and figure design: MC, HZ, JL, DL and JZ; and supervision of the prepared manuscript: JW and WL. All the authors verified the conclusion and approved the final version of the manuscript.

Acknowledgements

We thank all participants.

Disclosure statement

The authors report that there are no relevant conflicts of rights or interests.

Data availability statement

All information obtained by the authors in this manuscript can be found in the literature.

Additional information

Funding

This research was supported by Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation under Grant No. 2023GXNSFBA026040 and the Foundation of the Second Affiliated Hospital of Guangxi Medical University under Grant No. hbrc202104.