Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

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.

Histone Modifications and Their Targeting in Lymphoid Malignancies

“…Current research on HDAC6 is fueled by specific inhibitors like rocilinostat, which induces an unfolded protein response (UPR) in DLBCL cells concomitant with overloading of the proteasome [ 69 ]. Interestingly, HDAC6 inhibitor treatment of BL and DLBCL cell lines induced MYC degradation, which was accompanied by apoptosis and even prevented lymphomagenesis in Eµ-Myc mice [ 70 ]. Of note, HDAC6 seems to have cancer-specific functions as Hdac6 -knock-out mice showed no obvious phenotype under non-inflammatory conditions [ 71 , 72 ].…”

“…Of note, HDAC6 seems to have cancer-specific functions as Hdac6 -knock-out mice showed no obvious phenotype under non-inflammatory conditions [ 71 , 72 ]. This explains the relatively mild side effect profile observed after clinical administration of HDAC6 inhibitors [ 70 ], providing an argument for single HDAC member inhibition instead of using pan-HDACi.…”