RNA-binding protein hnRNPU regulates multiple myeloma resistance to selinexor.

Abstract

Multiple myeloma (MM) is an incurable haematological cancer. Selinexor is the first-in-class selective inhibitor of nuclear export (SINE) and was newly approved for the treatment of MM. Until now, very few studies have investigated selinexor resistance in MM. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is an RNA-binding protein and a component of hnRNP complexes. Here we found that hnRNPU regulates MM sensitivity to selinexor. Cell apoptosis assays were performed to compare selinexor-induced cell death in control knockdown (CTR-KD) and hnRNPU knockdown (hnR-KD) MM cells. HnRNPU knockdown-induced nuclear protein retention was examined by proteomics array. HnRNPU-conferred mRNA translation regulation was evaluated by sucrose gradient assay, RNA electrophoresis mobility shift assay, and RNA pull-down assay. We found that hnR-KD MM cells were more sensitive to selinexor-induced cell death in vitro and in mouse model. MM patients who responded to selinexor had relatively low hnRNPU expression. In brief, hnRNPU comprehensively regulated MM sensitivity to selinexor by affecting the localization of LTV1 and NMD3, and mRNA translation of MDM2 and RAN, which were involved in XPO1-mediated nuclear export of ribosome subunits and tumor suppressors. Our discoveries indicate that hnRNPU might be a possible marker to categorize MM patients for the use of Selinexor.

• Authors: Xin Wang, Juan Xu, Qun Li, Yue Zhang, Zhimei Lin, Xinyu Zhai, Fangfang Wang, Jingcao Huang, Qianwen Gao, Jingjing Wen, Linfeng Li, Yu Feng, Hongmei Luo, Qian Li, Xiang Liu, Junying Li, Fei Zhao, Li Zhang, Ting Niu, Chunyan Sun, Yuhuan Zheng
• Journal: Cancer letters (Cancer Lett) Vol. 580 Pg. 216486 (01 01 2024) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 37984724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023. Published by Elsevier B.V.

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein U
• Hydrazines
• Karyopherins
• NMD3 protein, human
• RNA
• RNA-Binding Proteins
• selinexor
• HNRNPU protein, human

Topics

• Animals
• Humans
• Mice
• Cell Line, Tumor
• Heterogeneous-Nuclear Ribonucleoprotein U
• Hydrazines (pharmacology)
• Karyopherins (genetics)
• Multiple Myeloma (drug therapy, genetics, metabolism)
• RNA
• RNA-Binding Proteins (genetics)