Another Reason to Eat Your Broccoli: Naturally Occurring Isothiocyanates Inhibit Deubiquitinating Enzymes

Abstract

The chemoprotective effects of a diet rich in broccoli or kale has been appreciated for several decades. Such cruciferous vegetables are a rich source of isothiocyanates (ITCs) such as benzyl ITC (BITC) and phenethyl ITC (PEITC). Each of these ITCs have antiproliferative activity against various tumors and PEITC is in clinical trials for lung and oral cancers. However, the mechanism by which ITCs suppress carcinogenesis has been the subject of much debate and numerous potential targets have been proposed. Here we show that BITC and PEITC inhibit the deubiquitinating enzyme (DUB) USP9x in vitro and in living cells. Both ITC treatment and USP9x knockdown decrease the levels of the oncogenic proteins MCL1 and Bcr‐Abl kinase. BITC and PEITC also inhibit UCH37, a proteasome associated DUB involved in the degradation of many proteins. Competitive activity profiling in cells pre‐treated with these ITCs suggests that other DUBs may also be inhibited. Inhibition occurs at physiologically relevant concentrations and time scales, and thus can explain many of the anticancer properties of dietary ITCs.