Bestrophin-4 relays HES4 and interacts with TWIST1 to suppress epithelial-to-mesenchymal transition in colorectal cancer cells.

Bestrophin isoform 4 () is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of + mature colonocytes in humans. However, if the role of is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumour growth and the liver metastasis in vivo. BEST4 is co-expressed with hairy/enhancer of split 4 () in the nucleus of cells, and HES4 signals by interacting with the upstream region of the promoter. is epistatic to and downregulates TWIST1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumour growth and induces EMT. Furthermore, the low level of the mRNA is correlated with advanced and the worse prognosis, suggesting its potential role involving CRC progression.