Orlistat targets NEDD8 conjugating enzyme UBC12 for cancer therapy

Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and one of the best-characterized drivers is oncogenic Wnt signaling. In this study, we demonstrated that Orlistat, an FDA-approved anti-obesity drug, is a unique inhibitor of oncogenic Wnt signaling and CRC. We confirmed that the known target FASN was not associated with Orlistat inhibition of CRC, and identified the NEDD8-conjugating enzyme UBC12 (UBE2M) as a candidate target instead. The direct engagement of Orlistat and UBC12 was confirmed by ITC assay with a KD value of 678 nM. Of note, Orlistat inhibited the NEDD8-conjugating activity of UBC12 and blocked UBC12 interaction with DCN1 (defective in cullin neddylation 1), thereby selectively suppressing Cullin 1 neddylation. In addition, overexpression of UBC12 positively regulated Wnt/β-catenin signaling in normal cells, while depletion of UBC12 not only inhibited oncogenic Wnt signaling but also abrogated Orlistat's inhibition of Wnt signaling and cell proliferation in CRC cells. Taken together, our findings revealed UBC12 as a novel Orlistat target, and identified UBC12 as a potential therapeutic target for Wnt-dependent cancers.