Histone deacetylase inhibitors regulate the proteasomal degradation of oncoproteins

Leukemogenesis is often linked to fusion proteins generated by chromosomal translocation products. Examples are AML1-ETO and PML-RARα which contribute to the pathogenesis of acute myeloid leukemia (AML). The work presented here reveals the novel insight that the turnover of both, AML1-ETO and PML-RARα, depends on the HDACi-inducible ubiquitin conjugase UBCH8 and the ubiquitin ligase SIAH1. Beyond showing that HDACi promote the degradation of oncoproteins, this work reveals that the ubiquitin ligase RLIM equally is a substrate for SIAH1. Thus, a formerly unknown hierarchical order of ubiquitin ligases affects the ubiquitin-proteasome system. Since constitutively activated mutant FMS-like tyrosine kinase 3 (FLT3-ITD) causally contributes to leukemic transformation and is frequently found in conjunction with AML1-ETO and PML-RARα in AML patients, it was also tested whether HDACi attenuate FLT3-ITD. Indeed, UBCH8 together with SIAH1 interact in a tyrosine phosphorylation-dependent way with FLT3-ITD and promote its proteasomal degradation. Accordingly, unstimulated wild-type FLT3 is hardly affected by HDACi. Thus, UBCH8, which has been implicated primarily in nuclear processes, could be identified as a novel important HDACi-inducible modulator of FLT3-ITD stability and leukemic cell survival. In summary, I could demonstrate in various AML cell lines and heterologous expression systems that UBCH8 and SIAH1 physically interact with and target FLT3-ITD, AML1-ETO, PML-RARα, and RLIM for proteasomal degradation. This work furthermore provides a deeper understanding on how enzymes promoting proteasomal degradation are regulated and how they interact with each other as well as with their cancer-relevant substrates. Conclusions presented here reveal novel biochemical mechanisms and molecular networks. In addition, they have implications for translational research.


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