RNF6,a RING-type ubiquitin ligase,has been identified as an oncogene in various cancers but its role in multiple myeloma (MM) remains elusive.In the present study we first showed that the expression levels of RNF6 in MM were significantly elevated compared with the bone marrow cells of healthy donors.Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation,whereas knockdown of RNF6 led to apoptosis of MM cells.Furthermore,we revealed that RNF6,as a ubiquitin ligase,interacted with glucocorticoid receptor (GR) and induced its K63-linked polyubiquitination.Different from current knowledge,RNF6 increased GR stability at both endogenous and exogenous contexts.Such an action greatly promoted GR transcriptional activity,which was confirmed by luciferase assays and by the increased expression levels of prosurvival genes including Bcl-xL and Mcl-1,two typical downstream genes of the GR pathway.Consistent with these findings,ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone,a typical anti-myeloma agent.In conclusion,we demonstrate that RNF6 promotes MM cell proliferation and survival by inducing atypical polyubiquitination to GR,and RNF6 could be a promising therapeutic target for the treatment of MM.