Selective molecular inhibition of the HDAC6 ZnF-UBP binding domain impairs multiple myeloma cell function
Abstract Multiple myeloma is a plasma cell malignancy with a poor prognosis despite the recent development of new therapeutic options. Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma cells and may be involved in the acquisition of resistance to conventional anti-proteasome treatme...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02465-1 |
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| Summary: | Abstract Multiple myeloma is a plasma cell malignancy with a poor prognosis despite the recent development of new therapeutic options. Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma cells and may be involved in the acquisition of resistance to conventional anti-proteasome treatments. In addition to displaying a deacetylase catalytic activity, HDAC6 plays an essential role in the regulation of autophagy and cell death by recognizing ubiquitinated motifs from misfolded proteins through its C-terminal ZnF-UBP binding domain. These defective proteins are sent to the aggresome to facilitate their degradation by autophagy. Here, we explore the role of the ZnF-UBP binding domain of HDAC6 in the function of multiple myeloma cells. A non-functional ZnF-UBP domain containing a 2-residue mutation in the binding site was designed, and the absence of ubiquitin binding was confirmed in a cell-free assay. Molecular docking simulations and electrostatic calculations revealed a significant decrease in the electrostatic potential of the mutated peptide, which is crucial for the stability of the complex with ubiquitin. A multiple myeloma cell line containing the non-functional ZnF-UBP domain was then engineered. Although the deacetylase activity of HDAC6 was maintained in these cells, they showed reduced cell growth, impaired aggresome formation, and a dysregulated gene expression profile that was more pronounced than cells entirely deficient in HDAC6. These results indicate that a non-functional ZnF-UBP binding domain impacts the function of multiple myeloma cells. Based on these findings, a series of quinazolinylpropanoic acid derivatives was synthesized to explore the inhibitory activity of small molecules to this domain. We propose that ZnF-UBP binding domain inhibitors should be further evaluated as potential therapeutic agents in multiple myeloma. |
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| ISSN: | 2058-7716 |