ZNF276 and WIZ are CRBN neosubstrates involved in the anti-angiogenic activity of thalidomide and immunomodulatory drugs

Abstract

Abstract Thalidomide was once developed as a sedative but had been withdrawn from the market in the 1960s because of its serious teratogenicity. Currently, this drug is reevaluated and used for the treatment of multiple myeloma, and many derivatives such as lenalidomide and pomalidomide have been developed. CRBN is a primary target of thalidomide and its derivatives and forms an E3 ubiquitin ligase complex with DDB1 and CUL4. Although the basic mechanism of action of thalidomide is quite well understood, a long-standing question remains regarding its inhibitory effect on angiogenesis. Here, we employed a comprehensive proteomic approach using thalidomide-treated endothelial cells to identify ZNF276 and WIZ as CRBN neosubstrates. Thalidomide and its derivatives exert their anti-angiogenic effects through these two zinc finger proteins, resulting in the downregulation of FABP4. This study reveals the CRBN neosubstrates involved in thalidomide-induced anti-angiogenesis and provides attractive therapeutic targets of CRBN-based protein degraders.