DHX33 inhibitors induced transcriptional changes for a subset of genes in cancer cells

RNA helicase DHX33 has been shown to regulate many genes involved in Cancer development. Whether or not this depends on its helicase activity remains a question. Two previously developed small molecules, BCD38 and KY386, have been shown to inhibit DHX33 helicase activity in vitro. Of them, KY386 is more potent to inhibit Cancer development in vitro and in vivo. In this study, BCD38 and KY386, were both used to evaluate gene transcriptional changes upon DHX33 helicase inhibition. The effect was then compared to that of DHX33 knockdown. What was found was that DHX33 inhibitors caused transcriptional changes for a subset of genes, which recapitulated DHX33 knockdown in human Cancer cells, albeit with some discrepancy. DHX33 inhibitors selectively downregulated a subset of genes involved in Cancer progression in vitro and in vivo. Our study for the first time reveals that specific targeting DHX33 helicase activity with small molecule inhibitors induced gene transcriptional changes, which mimicked the effect the DHX33 knockdown, implicating that the cellular functions of DHX33 is dependent on its helicase activity.