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

Abstract

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.

RETRACTED: Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies

“…The HDAC6 inhibitor ricolinostat has been found to induce an unfolded protein response and overload the proteasome in DLBCL cells [ 188 ]. Moreover, the HDAC6 inhibitor treatment of DLBCL and B-cell lymphoma cells in Eµ-Myc mice induced MYC degradation, apoptosis, and inhibition of lymphomagenesis [ 189 ].…”

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

“…Interestingly, in the Chalcone case, both effects led to anticancer activity. Posttranslational modifications of Hsp40 (farnesylation) and its binding partners (acetylated tubulin) were also described as targetable Hsp40-modulatory mechanisms [ 125 , 131 , 132 , 133 ]. In this way, potential combination partners such as farnesyltransferase inhibitors and HDAC6 inhibitors emerged as modulators of the Hsp70-Hsp40 axis, which might be considered for future in vivo experiments.…”

“…Selective inhibition of cytoplasmic HDAC6 by the HDAC6 inhibitor 34 ( Figure 5 , marbostat) led to MYC degradation and apoptosis in MYC-overexpressing B-cell lymphoma cells. It was shown that HDAC6 inhibition by compound 34 led to hyperacetylation of tubulin followed by enhanced binding of DNAJA3 to hyperacetylated tubulin in the cytoplasm of B-cell lymphoma cells, which led to enhanced Myc degradation [ 133 ].…”

Role of Rad18 in B cell activation and lymphomagenesis

“…To generate experimentally used WT and KO mice, RD and RDF mice were bred to be heterozygous for Rad18. To obtain Rad18;delCre; Eµ–Myc (RDM) and Rad18;DelCre;FlpE;Emμ-myc (RDFM) mouse lines, RD and RDF mouse lines were crossed with heterozygous mice regarding Eµ–Myc on a C57BL/6 background 39 , originally provided from Jackson Laboratory. Mice developing tumours were immediately sacrificed via cervical dislocation after reaching humane end point criteria.…”