Abstract
Overexpression of oncogenic MYC is the hallmark of many lymphomas and is related to a poor prognosis. Although MYC is a potential cancer driver, therapeutic targeting is still challenging. Here, we report that histone deacetylase 6 (HDAC6) inhibition using the novel inhibitor Marbostat-100 (M-100) specifically alters protein-protein interactions in MYC-dependent cancer cells and targets MYC for proteasomal degradation. Subsequently, massive apoptosis is induced in MYC-overexpressing B-cell lymphoma cells after M-100 treatment. Besides, the application of M-100 prevents lymphoma formation in Eμ-Myc transgenic mice and efficiently slows down tumor growth in already manifested lymphomas. Moreover, M-100 exclusively targets MYC-dependent tumor cells with little or no side effects on non-tumor cells and tissues. HDAC6 inhibition results in pleiotropic cellular effects, such as hyperacetylation of Tubulin. We propose a mechanism where the heat-shock protein DNAJA3 associates with acetylated Tubulin to control MYC turnover in malignant cells. Our data show a new mechanism how HDAC6 inhibition targets oncogenic MYC in lymphomas and demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial support R.W. was supported by a scholarship from the Carl Zeiss Foundation. C.K. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), GRK 1715. Work done in the group of O.H.K. was done by M.B. and funded by DFG, Project-ID 393547839 – SFB 1361 and DFG, GRK 2291/9-1.
Disclosure of conflicts of interest The authors declare no potential conflicts of interest.