Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

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.