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The ubiquitin binding domain of HDAC6 : a key regulator of aggresomal protein disposal and new therapeutic target to combat multiple myeloma

Book Contribution - Book Abstract Conference Contribution

Multiple myeloma (MM) is a deadly and incurable haematological cancer, characterized by the accumulation of abnormal plasma cells in the bone marrow. In addition, current MM therapy evokes many adverse side effects. We aim to provide a new therapeutic opportunity against MM , with less side effects to improve the quality of life of MM patients, by harnessing the protein degradation system. The proteasome degrades misfolded proteins to prevent toxic accumulation and to maintain cellular homeostasis. Since MM cells secrete large amounts of an abnormal antibody, they are highly dependent on this disposal system for their survival. This weakness has successfully been exploited by proteasome inhibitors (PIs) as Bortezomib. However, when the proteasome function is compromised, the aggresome can serve as an alternative route, thereby contributing to resistance to PI therapy. Therefore, simultaneous inhibition of both the proteasome and the aggresome may represent a promising strategy to enhance apoptosis in cancer cells, to alleviate PI-related side effects by lowering the PI dose and to overcome resistance to PI therapy. Histone deacetylase 6 (HDAC6) is a member of the histone deacetylase family of enzymes, that plays a prominent role in aggresome formation. More specifically, HDAC6 binds aggregated polyubiquitinated proteins through its zinc finger ubiquitin binding domain (ZUB) and mediates trafficking via the microtubule to the aggresome, rendering this isozyme an important target to combat MM when combined with PIs. Therefore, we aim to design, synthesize and biologically evaluate inhibitors of the HDAC6 ZUB in the context of MM.
Book: OncoPoint Symposium, 8th, Abstracts
Number of pages: 1
Publication year:2022
Accessibility:Open