FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells

Abstract

Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by Forkhead box subclass M1 (FOXM1) as a co-factor to transactivate FOXM1 target genes in a kinase-independent manner. In addition, we show that AURKA and FOXM1 participate in a tightly coupled positive feedback loop to enhance BCSC phenotype. Indeed, kinase-dead AURKA can effectively transactivate the FOXM1 promoter through a Forkhead response element, whereas FOXM1 can activate AURKA expression at the transcriptional level in a similar manner. Consistently, breast cancer patient samples portrayed a strong and significant correlation between the expression levels of FOXM1 and AURKA. Moreover, both FOXM1 and AURKA were essential for maintaining the BCSC population. Finally, we demonstrated that the AURKA inhibitor AKI603 and FOXM1 inhibitor thiostrepton acted synergistically to inhibit cytoplasmic AURKA activity and disrupt the nuclear AURKA/FOXM1-positive feedback loop, respectively, resulting in a more effective inhibition of the tumorigenicity and self-renewal ability of BCSCs. Collectively, our study uncovers a previously unknown tightly coupled positive feedback signalling loop between AURKA and FOXM1, crucial for BCSC self-renewal. Remarkably, our data reveal a novel potential therapeutic strategy for targeting both the cytoplasmic and nuclear AURKA function to effectively eliminate BCSCs, so as to overcome both breast cancer and drug resistance.

Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis

“…High FOXM1 expression was detected in CSCs and TICs. FOXM1 promoted the proliferation and maintenance of breast [28,43], hepatocellular [44], pancreatic [45], and lung CSCs [46], and FOXM1 depletion repressed the stemness of these cancer cells. FOXM1 is an important component of the reprogramming network and functions together with reprogramming transcriptional factors, such as OCT4, SOX2, and KLF4, to regulate CSC self-renewal and maintenance [47,48].…”

“…Recent studies have suggested that FOXM1 plays a critical role in maintaining the CSC self-renewal and tumorigenic potential [28], and FOXO3a can bind to the promoter of FOXM1 to suppress its transcription [29,30]. Therefore, we evaluated whether FOXO3a affects BCSC properties by controlling FOXM1 signaling.…”

Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis

“…AURKA has been studied in a wide range of human malignancies and is associated with poor prognosis in several malignancies, including cervical squamous cell carcinoma, hepatocellular carcinoma, and nonsmall cell lung carcinoma (Ma et al, ; Wang et al, ; Zheng et al, ). Besides, Yang et al, () reported that AURKA as a transactivating co‐factor in the induction of the c‐Myc oncoprotein in breast cancer stem cells (BCSCs). In CRC, AURKA is critical for chromosome 20q amplification‐associated malignant transformation in colorectal adenomas (Chuang et al, ).…”

MERTK Promotes Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors in Non–small Cell Lung Cancers Expressing Wild-type EGFR Family Members

“…FOX subclass M1 (FOXM1), an oncogenic transcription factor involved in drug resistance, is regulated downstream of PI3K-AKT and MAPK-ERK and activates AURKA expression. In turn, AURKA functions as a cofactor allowing kinase-independent transactivation of FOXM1 target genes (45).…”