Abstract:
Precursor mRNA (pre-mRNA) splicing is a crucial step in eukaryotic gene expression catalysed by a highly complex ribonucleoprotein assembly known as the spliceosome. Abnormal splicing activity or mutation in spliceosome components, including the splicing factor 3B subunit 1 (SF3B1) have been reported to be associated with cancer. This has led to the identification and development of potential anti-cancer agents
which target and modulate SF3B1. Vitamin D is an essential nutrient as well as a potent steroid hormone that regulates a broad spectrum of physiological processes in the human body. The human body can synthesize vitamin D via ultraviolet exposure from the sunlight. A wide range of studies show that vitamin D being an anti-cancer agent not only controls calcium metabolism, it also elicits a wide variety of biological responses which regulates cellular proliferation, cell growth and apoptosis. In addition, recent studies have revealed that vitamin D exerts its biological action via the presence of vitamin D receptor (VDR). Using Maestro 11.1, we predicted the binding site and performed a virtual screening on SF3B1 crystal structure (PDB ID: 5IFE). Notably, vitamin D and analogues, i.e. calcitriol and calcipotriol appeared as top ranked SF3B1 inhibitors. We also showed the specificity of vitamin D and analogues on treated breast
carcinoma cells undergoing apoptosis without having much effects on normal breast cells. In addition to its anticancer properties, our finding also demonstrated vitamin D and analogues treatment resulted in significant increase of un-spliced pre-mRNAs and reduced SF3B1 protein expression as well as affecting other components of SF3B family, i.e. SF3B3 and SF3B4 suggesting that vitamin D and analogues could potentially inhibit splicing activity. Finally, we also showed knock-down of VDR rescued vitamin D suppression of SF3B1 expression, suggesting that the inhibition of SF3B1 by vitamin D is VDR-dependent. In summary, our findings identified vitamin D and analogues as potential SF3B1 inhibitors which warrants further investigations.
