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

Winkler, R.; Mägdefrau, A.-S.; Kleemann, M.; Beyer, M.; Linke, K.; Hansen, L.; Schaffer, A.-M.; Hoffmann, M. E.; Poepsel, S.; Heyd, F.; Beli, P.; Möröy, T.; Mahboobi, S.; Krämer, O. H.; Kosan, C.

doi:10.1101/2021.06.01.445760

bioRxiv · 10.1101/2021.06.01.445760

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

Winkler, R.·Mägdefrau, A.-S.·Kleemann, M.·Beyer, M.·Linke, K.·Hansen, L.·Schaffer, A.-M.·Hoffmann, M. E.·Poepsel, S.·Heyd, F.·Beli, P.·Möröy, T.·Mahboobi, S.·Krämer, O. H.·Kosan, C.

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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.

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Winkler, R., Mägdefrau, A.-S., Kleemann, M., Beyer, M., Linke, K., Hansen, L., Schaffer, A.-M., Hoffmann, M. E., Poepsel, S., Heyd, F., Beli, P., Möröy, T., Mahboobi, S., Krämer, O. H., Kosan, C.. 2021-06-01. Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition. https://doi.org/10.1101/2021.06.01.445760

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