Winkler, Rene and Magdefrau, Ann-Sophie and Piskor, Eva-Maria and Kleemann, Markus and Beyer, Mandy and Linke, Kevin and Hansen, Lisa and Schaffer, Anna-Maria and Hoffmann, Marina E. and Poepsel, Simon and Heyd, Florian and Beli, Petra and Moroy, Tarik and Mahboobi, Siavosh and Kramer, Oliver H. and Kosan, Christian (2022) Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition. ONCOGENE, 41 (40). pp. 4560-4572. ISSN 0950-9232, 1476-5594
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | UBIQUITIN-MEDIATED PROTEOLYSIS; C-MYC; DOWN-REGULATION; HDAC6; CANCER; TUBULIN; ACETYLATION; EXPRESSION; LINES; NOXA; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2024 08:17 |
| Last Modified: | 01 Feb 2024 08:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58457 |
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