Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition
Winkler, René (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Mägdefrau, A.S. (Friedrich Schiller University Jena)
Piskor, E.M. (Friedrich Schiller University Jena)
Kleemann, M. (Friedrich Schiller University Jena)
Beyer, M. (University Medical Center Mainz)
Linke, K. (Friedrich Schiller University Jena)
Hansen, L. (Friedrich Schiller University Jena)
Schaffer, A.M. (Friedrich Schiller University Jena)
Hoffmann, M.E. (Institute of Molecular Biology)
Poepsel, S. (University of Cologne)
Heyd, F. (Freie Universität Berlin)
Beli, P. (Institute of Molecular Biology)
Möröy, T. (Institut de Recherches Cliniques de Montréal)
Mahboobi, S. (University of Regensburg)
Krämer, O.H. (University Medical Center Mainz)
Kosan, C. (Friedrich Schiller University Jena)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	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.
Nota:	RW was supported by a scholarship from the Carl Zeiss Foundation. CK received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), GRK 1715. E-MP was supported by a Landesgraduiertenstipendium (Friedrich Schiller University Jena). Work done in the group of OHK was done by MB and is funded by DFG, Project-ID 393547839-SFB 1361 and DFG, GRK 2291/9-1, project number 427404172. Open Access funding enabled and organized by Projekt DEAL.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Acetylation ; Animals ; Heat-Shock Proteins ; Histone Deacetylase 6 ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; HSP40 Heat-Shock Proteins ; Humans ; Lymphoma, B-Cell ; Mice ; Transcription Factors ; Tubulin
Publicat a:	Oncogene, Vol. 41 Núm. 40 (30 2022) , p. 4560-4572, ISSN 1476-5594

DOI: 10.1038/s41388-022-02450-3
PMID: 36068335

13 p, 2.7 MB

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