The bone marrow microenvironment where multiple myeloma (MM) originated is hypoxic and an important stimulus for initiation of drug resistance to chemotherapies, but the underlying mechanisms and key regulators are still indistinct. In the current study, we found that hypoxia stimulus easily induced chemoresistance to proteasome inhibitors (PIs) but not to other chemicals, and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein

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... actome analysis identified SENP1 as a key modifier of SRC-3 stability, as deSUMOylation by SENP1 attenuated the K11-linked polyubiquitination of SRC-3. Depletion of SENP1 in MM cells by CRISPR/cas9 sgRNA, or in SENP1fl/flCD19Cre/+ B cells, accelerated the degradation of SRC-3, and overcame the resistance to PIs at vast scale, which phenotype was similar to administration of SENP1inhibitor Momordin Ιc (Mc) in the Vk*Myc and 5TGM1 mouse models and patient derived xenograft (PDX) of myeloma. Importantly, SENP1 level was positively correlated with SRC-3 level in the tissues from refractory/relapsed MM, as well as in xenograft tissues from mice treated with bortezomib and Mc. Taken together, our findings suggest that hypoxia induced SENP1 is a crucial regulator of chemoresistance to PIs, and shed light on developing therapeutic strategies to overcome chemoresistance by using small molecules targeting SENP1 or SRC-3.