A bacterial protease depletes c-MYC and increases survival in mouse models of bladder and colon cancer. Butler Daniel S C,Cafaro Caterina,Putze Johannes,Wan Murphy Lam Yim,Tran Thi Hien,Ambite Ines,Ahmadi Shahram,Kjellström Sven,Welinder Charlotte,Chao Sing Ming,Dobrindt Ulrich,Svanborg Catharina Nature biotechnology Is the oncogene MYC upregulated or hyperactive? In the majority of human cancers, finding agents that target c-MYC has proved difficult. Here we report specific bacterial effector molecules that inhibit cellular MYC (c-MYC) in human cells. We show that uropathogenic Escherichia coli (UPEC) degrade the c-MYC protein and attenuate MYC expression in both human cells and animal tissues. c-MYC protein was rapidly degraded by both cell-free bacterial lysates and the purified bacterial protease Lon. In mice, intravesical or peroral delivery of Lon protease delayed tumor progression and increased survival in MYC-dependent bladder and colon cancer models, respectively. These results suggest that bacteria have evolved strategies to control c-MYC tissue levels in the host and that the Lon protease shows promise for therapeutic targeting of c-MYC in cancer. 10.1038/s41587-020-00805-3