Here we report that(i) Aur shows proteasome-inhibitory effect that is comparable to that ofbortezomib/Velcade (Vel); (ii) different from bortezomib, Aur inhibitsproteasome-associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20Sproteasome; (iii) inhibition of the proteasome-associated DUBs is required forAur-induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth invivo and induces cytotoxicity in cancer cells from acute myeloid leukemiapatients. Here, USP14 is linked to neoplasm.