Journal
CANCER LETTERS
Volume 567, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2023.216262
Keywords
NF-Y; Alternative splicing; CCAAT; Colon cancer; Cell migration; Metastasis; EMT; ECM; E-Cadherin
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Aberrant splicing of NF-YAl transcript is associated with aggressive mesenchymal CRC and predicts shorter survival. CRC cells overexpressing NF-YAl exhibit altered cell behavior and transcription of genes involved in cell adhesion and epithelial-mesenchymal transition. These findings suggest that NF-YAl may serve as a prognostic factor for CRC and splice-switching strategies could be used to reduce metastatic progression.
Aberrant splicing events are associated with colorectal cancer (CRC) and provide new opportunities for tumor diagnosis and treatment. The expression of the splice variants of NF-YA, the DNA binding subunit of the tran-scription factor NF-Y, is deregulated in multiple cancer types compared to healthy tissues. NF-YAs and NF-YAl isoforms differ in the transactivation domain, which may result in distinct transcriptional programs. In this study, we demonstrated that the NF-YAl transcript is higher in aggressive mesenchymal CRCs and predicts shorter patients' survival. In 2D and 3D conditions, CRC cells overexpressing NF-YAl (NF-YAlhigh) exhibit reduced cell proliferation, rapid single cell amoeboid-like migration, and form irregular spheroids with poor cell-to-cell adhesion. Compared to NF-YAshigh , NF-YAlhigh cells show changes in the transcription of genes involved in epithelial-mesenchymal transition, extracellular matrix and cell adhesion. NF-YAl and NF-YAs bind similarly to the promoter of the E-cadherin gene, but oppositely regulate its transcription. The increased metastatic potential of NF-YAlhigh cells in vivo was confirmed in zebrafish xenografts.These results suggest that the NF-YAl splice variant could be a new CRC prognostic factor and that splice-switching strategies may reduce metastatic CRC progression.
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