Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition
Por:
Winkler, R, Magdefrau, AS, Piskor, EM, Kleemann, M, Beyer, M, Linke, K, Hansen, L, Schaffer, AM, Hoffmann, ME, Poepsel, S, Heyd, F, Beli, P, Moroy, T, Mahboobi, S, Kramer, OH and Kosan, C
Publicada:
30 sep 2022
Ahead of Print:
1 sep 2022
Resumen:
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.
Filiaciones:
:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Josep Carreras Leukaemia Res Inst IJC, Campus ICO Germans Trias & Pujol, Badalona 08916, Spain
Magdefrau, AS:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Piskor, EM:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Kleemann, M:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Beyer, M:
Univ Med Ctr Mainz, Inst Toxicol, D-55131 Mainz, Germany
Linke, K:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Hansen, L:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Schaffer, AM:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Hoffmann, ME:
Inst Mol Biol IMB, D-55128 Mainz, Germany
Poepsel, S:
Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany
Univ Cologne, Univ Hosp, D-50931 Cologne, Germany
Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany
Heyd, F:
Free Univ Berlin, Inst Chem & Biochem, Lab RNA Biochem, D-14195 Berlin, Germany
Beli, P:
Inst Mol Biol IMB, D-55128 Mainz, Germany
Moroy, T:
Inst Rech Clin Montreal IRCM, Montreal, PQ H2W 1R7, Canada
Mahboobi, S:
Univ Regensburg, Inst Pharm, Dept Pharmaceut Med Chem 1, D-93040 Regensburg, Germany
Kramer, OH:
Univ Med Ctr Mainz, Inst Toxicol, D-55131 Mainz, Germany
Kosan, C:
Friedrich Schiller Univ, Ctr Mol Biomed CMB, Dept Biochem, D-07745 Jena, Germany
Green Published, hybrid, Green Submitted
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