Identification of NOVA family proteins as novel β-catenin RNA-binding proteins that promote epithelial-mesenchymal transition.

The NOVA (neuro-oncological ventral antigen) protein family, composed of two paralogs, NOVA1 and NOVA2, consists of RNA-binding proteins involving in processes such as alternative splicing and transport of some target mRNAs. The function of NOVA has been well studied, and increasing evidence has shown that NOVA proteins may be important contributors to carcinogenesis. However, the molecular mechanisms underlying the roles of NOVA proteins in carcinogenesis remain to be determined. Here, we have identified both NOVA1 and NOVA2 as novel β-catenin RNA-binding proteins. The NOVA1/NOVA2 heterodimer positively regulates β-catenin expression by enhancing β-catenin mRNA stability. Furthermore, we demonstrated that NOVA1 and NOVA2 promote epithelial-mesenchymal transition via β-catenin in breast cancer cells, as NOVA-induced upregulation of epithelial and mesenchymal marker expression was attenuated by restoring β-catenin expression. Our results advance the current understanding of β-catenin post-transcriptional regulation and shed light on the role of NOVA proteins in cancer, suggesting that NOVA proteins are potential therapeutic targets in breast cancer.