Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma.

Abstract

The bone marrow microenvironment in multiple myeloma (MM) is hypoxic and provides multi-advantages for the initiation of chemoresistance, 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), and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein interactome analysis identified SENP1 as a key modifier of SRC-3 stability, as SENP1-mediated deSUMOylation attenuated the K11-linked polyubiquitination of SRC-3. SENP1 depletion in the SENP1fl/flCD19Cre/+ B cells showed impaired SRC3 stability, and knockdown of SENP1 in MM cells by CRISPR/cas9 sgRNA accelerated the degradation of SRC-3 and remarkably overcame the resistance to PIs. In the Vk*Myc and 5TGM1 mouse models as well as patient-derived xenograft (PDX) of myeloma, SENP1 inhibitor Momordin Ιc (Mc) increased the sensitivity to PIs in MM cells. 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.

• Authors: Jing Guo, Yangyang Lv, Sheng Wang, Ziyi Peng, Ying Xie, Yixuan Wang, Hongmei Jiang, Xin Li, Mengqi Wang, Meilin Hu, Jiangpeng Mu, Jingya Wang, Yangyang Xie, Xiankui Cheng, Zhigang Zhao, Zhiqiang Liu
• Journal: Oncogene (Oncogene) Vol. 41 Issue 45 Pg. 4971-4979 (11 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 36209257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Proteasome Inhibitors
• Nuclear Receptor Coactivator 3
• Cysteine Endopeptidases

Topics

• Humans
• Mice
• Animals
• Proteasome Inhibitors (pharmacology)
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Nuclear Receptor Coactivator 3 (genetics, metabolism)
• Cell Line, Tumor
• Cysteine Endopeptidases (metabolism)
• Drug Resistance, Neoplasm
• Ubiquitination
• Hypoxia
• Tumor Microenvironment