RNF6 activates the AKT/mTOR signaling pathway by inhibiting PTEN via K27-linked polyubiquitination in myeloma.

As the second most hematological malignancy, multiple myeloma (MM) is closely associated with dysregulated AKT/mTOR signaling. However, the underlying mechanism remains unclear. In the present study, we find the AKT/mTOR signaling pathway is activated by the ring finger protein RNF6. Acting as a ubiquitin ligase, RNF6 binds to and mediates PTEN polyubiquitination, altering its stability. Further investigations reveal that RNF6 specifically induces K27-linked ubiquitination of PTEN. RNF6 also prevents PTEN from translocalization to the plasma membrane, thereby inhibiting its phosphatase activity. Consistent with this finding, RNF6 promotes the production of PI(3,4,5)P3, and when PTEN is depleted, RNF6 fails to activate AKT/mTOR signaling. Moreover, we find USP39 binds to PTEN and abolishes K27-linked polyubiquitination mediated by RNF6. Furthermore, USP39 suppresses AKT/mTOR signaling transduction activated by RNF6. In addition, RNF6 is found to promote glycolysis in myeloma cells, but this effect is inhibited by USP39. Lastly, we discovered that oleandrin, a natural product, induces K48-linked polyubiquitination of RNF6 and subsequent degradation, thereby suppressing PTEN with K27-linked polyubiquitination and the AKT/mTOR signaling pathway. In conclusion, the study identifies RNF6 and USP39 as novel ubiquitin ligases or deubiquitinases responsible for K27-linked polyubiquitination of PTEN and as novel modulators of the AKT/mTOR pathway. Targeting the RNF6/PTEN/AKT/mTOR signaling axis might represent a novel therapeutic strategy for myeloma treatment.