ABSTRACT
The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4CRBN. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.
Subject(s)
Antineoplastic Agents/pharmacology , Multiple Myeloma/metabolism , Thalidomide/analogs & derivatives , Transcription Factors/metabolism , Ubiquitin-Protein Ligases/metabolism , Antineoplastic Agents/metabolism , Cell Line, Tumor , Chromosomal Proteins, Non-Histone/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Gene Expression Regulation/drug effects , Gene Knockdown Techniques , Humans , Lenalidomide/pharmacology , Multiple Myeloma/drug therapy , Mutation , Protein Binding , Proteolysis/drug effects , RNA, Messenger , RNA, Small Interfering , Thalidomide/metabolism , Thalidomide/pharmacology , Time Factors , Transcription Factors/genetics , UbiquitinationABSTRACT
The EF-hand is a helix-loop-helix motif observed mainly in intracellular calcium binding proteins. The EF-hand usually occurs as a pair, EF-lobe, which is a unit of evolution and structure. Penta EF-hand (PEF) proteins form a unique group including calpain, sorcin, grancalcin, ALG-2, and peflin. The fifth EF-hand of PEF proteins makes a pair with that of another PEF protein. The members of PEF family have diverse functions and their evolution is complex. The interaction of PEF proteins with target occurs at several sites. Here, we analyzed the ancestral sequences of each group of PEF proteins and determined the interfaces for the specific and selective interaction to the target among several PEF proteins. The shape of the groove for interaction at common site is different among PEF proteins. We found that the changes at limited sites induced the divergence of interaction sites that determines the selectivity of targets. The residues involved the changes at limited sites are important for the drug design selective to each PEF protein.
