ArticleJournal of orthopaedic surgery and research2025
A novel mechanism in regulating drug sensitivity, growth, and apoptosis of bortezomib-resistant multiple myeloma cells: the USP4/KLF2/HMGA2 cascade.
Article in Journal of orthopaedic surgery and research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Kinetics of MM1.S Multiple Myeloma Cells in a 3D Polymer Particle Culture System with Bone Marrow Stromal Cells and Bortezomib.Pharmaceuticals (Basel, Switzerland) · 2026Article
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8 authors.
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Abstract
backgroundMultiple myeloma (MM) is a malignant disorder originating from plasma cells. Bortezomib (BTZ) resistance has become a huge obstacle to MM treatment. Herein, we elucidated the action of Kruppel-like factor 2 (KLF2), a crucial transcription factor (TF), on BTZ resistance of MM.
methodsTwo BTZ-resistant cell lines (MM1.S/BTZ and NCI-H929/BTZ) were generated and used. KLF2 mRNA was quantified by quantitative PCR, and protein expression was analyzed by immunoblotting. MTT cell cytotoxicity assay was used to test BTZ sensitivity. Cell growth was detected by MTT and EdU assays. Flow cytometry was used for apoptosis and cycle distribution analyses. The USP4/KLF2 relationship was examined by Co-IP and protein stability assays. The KLF2/HMGA2 interplay was confirmed by luciferase and ChIP assays.
resultsUpregulation of KLF2 was observed in MM serum and BTZ-resistant MM cells. Depletion of KLF2 suppressed cell growth and enhanced apoptosis and BTZ sensitivity in MM1.S/BTZ and NCI-H929/BTZ cells. Moreover, USP4 increased the stability of KLF2 protein by deubiquitination and affected cell growth, apoptosis and BTZ sensitivity via KLF2. KLF2 functioned as a regulator of HMGA2 transcription and modulated cell growth, apoptosis and BTZ sensitivity through HMGA2. Additionally, USP4 modulated HMGA2 expression via KLF2 in the two BTZ-resistant cell lines.
conclusionOur study demonstrates the crucial role of the USP4/KLF2/HMGA2 cascade in regulating cell growth, apoptosis and BTZ sensitivity in BTZ-resistant MM cells, providing novel targets for improving anti-MM efficacy of BTZ.
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