Inhibition of RNA Binding in SND1 Increases the Levels of miR-1-3p and Sensitizes Cancer Cells to Navitoclax

SIMPLE SUMMARY: Despite of decades of intensive research, several cancer types, for example aggressive colon cancers, are still difficult to treat, and life expectancy is low. Since cancer cells are often resilient and tolerate chemical stresses such as cancer drugs efficiently, they have been difficult to treat. Therefore, combined treatment methods that target cancer cells’ stress tolerance may enhance the treatment outcome. Here we have shown that certain cancer drugs are more effective in colon cancer cells when the expression of a protein called SND1, implicated in regulation of stress responses, is prevented in those cells. We also found that a drug compound called suramin binds to a certain “pocket” of an SND1 protein, and this prevents the interaction of SND1 and certain small RNA molecules, called microRNAs. This block of SND1-microRNA interaction reduces the resilience of colon cancer cells and thus sensitizes them to cancer treatment. ABSTRACT: SND1 is an RNA-binding protein overexpressed in large variety of cancers. SND1 has been proposed to enhance stress tolerance in cancer cells, but the molecular mechanisms are still poorly understood. We analyzed the expression of 372 miRNAs in the colon carcinoma cell line and show that SND1 silencing increases the expression levels of several tumor suppressor miRNAs. Furthermore, SND1 knockdown showed synergetic effects with cancer drugs through MEK-ERK and Bcl-2 family-related apoptotic pathways. To explore whether the SND1-mediated RNA binding/degradation is responsible for the observed effect, we developed a screening assay to identify small molecules that inhibit the RNA-binding function of SND1. The screen identified P2X purinoreceptor antagonists as the most potent inhibitors. Validation confirmed that the best hit, suramin, inhibits the RNA binding ability of SND1. The binding characteristics and mode of suramin to SND1 were characterized biophysically and by molecular docking that identified positively charged binding cavities in Staphylococcus nuclease domains. Importantly, suramin-mediated inhibition of RNA binding increased the expression of miR-1-3p, and enhanced sensitivity of cancer cells to Bcl-2 inhibitor navitoclax treatment. Taken together, we demonstrate as proof-of-concept a mechanism and an inhibitor compound for SND1 regulation of the survival of cancer cells through tumor suppressor miRNAs.