As a protein critical for the maintenance of DNA methylation and cell proliferation,UHRF1 is frequently highly expressed in various human cancers and is considered as a drug target for cancer therapy.In a high throughput screening for small molecules that induce UHRF1 protein degradation,we have identified the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin(17-AAG).We present evidence that UHRF1 interacts with Hsp90 chaperone complex and is a novel Hsp90 client protein.Pharmacological inhibition of Hsp90 with 17-AAG or 17-DMAG results in UHRF1 ubiquitination and proteasome-dependent degradation.Interestingly this Hsp90 inhibitor-induced UHRF1 degradation is independent of CHIP and CUL5,two previously identified ubiquitin E3 ligases for Hsp90 client proteins.In addition,this degradation is dependent neither on the UHRF1s intrinsic E3 ligase nor the E3 ligase SCFβ-TrCP that has been implicated in regulation of UHRF1 stability.We also provide evidence that Hsp90 inhibitors may suppress cancer cell proliferation in part through its induced UHRF1 degradation.Taken together,our results identify UHRF1 as a novel Hsp90 client protein and shed light on the regulation of UHRF1 stability and function.