Winkler, Rene, Magdefrau, Ann-Sophie, Piskor, Eva-Maria, Kleemann, Markus, Beyer, Mandy, Linke, Kevin, Hansen, Lisa, Schaffer, Anna-Maria ORCID: 0000-0002-2561-0820, Hoffmann, Marina E., Poepsel, Simon ORCID: 0000-0002-8304-4062, Heyd, Florian, Beli, Petra, Moroy, Tarik, Mahboobi, Siavosh, Kramer, Oliver H. and Kosan, Christian (2022). Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition. Oncogene, 41 (40). S. 4560 - 4573. LONDON: SPRINGERNATURE. ISSN 1476-5594

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Winkler, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Magdefrau, Ann-SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piskor, Eva-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleemann, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beyer, MandyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linke, KevinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaffer, Anna-MariaUNSPECIFIEDorcid.org/0000-0002-2561-0820UNSPECIFIED
Hoffmann, Marina E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poepsel, SimonUNSPECIFIEDorcid.org/0000-0002-8304-4062UNSPECIFIED
Heyd, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beli, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moroy, TarikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahboobi, SiavoshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kramer, Oliver H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kosan, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-690354
DOI: 10.1038/s41388-022-02450-3
Journal or Publication Title: Oncogene
Volume: 41
Number: 40
Page Range: S. 4560 - 4573
Date: 2022
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1476-5594
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UBIQUITIN-MEDIATED PROTEOLYSIS; C-MYC; DOWN-REGULATION; HDAC6; CANCER; TUBULIN; ACETYLATION; EXPRESSION; LINES; NOXAMultiple languages
Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69035

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