Journal Article

DKFZ-2020-01721

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma.

Ecker, J. (First author)DKFZ* ; Thatikonda, V.DKFZ* ; Sigismondo, G.DKFZ* ; Selt, F.DKFZ* ; Valinciute, G.DKFZ* ; Oehme, I.DKFZ* ; Müller, C.DKFZ* ; Buhl, J. L.DKFZ* ; Ridinger, J.DKFZ* ; Usta, D.DKFZ* ; Qin, N.DKFZ* ; van Tilburg, C. M.DKFZ* ; Herold-Mende, C. ; Remke, M.DKFZ* ; Sahm, F.DKFZ* ; Westermann, F.DKFZ* ; Kool, M.DKFZ* ; Wechsler-Reya, R. J. ; Chavez, L. ; Krijgsveld, J.DKFZ* ; Jäger, N.DKFZ* ; Pfister, S. M.DKFZ* ; Witt, O.DKFZ* ; Milde, T. (Last author)DKFZ*

2021
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/neuonc/noaa191

Abstract: The sensitivity of MYC amplified medulloblastoma to class I HDAC inhibition has been shown previously, however understanding the underlying molecular mechanism is crucial for selection of effective HDAC inhibitors for clinical use. The aim of this study was to investigate the direct molecular interaction of MYC and the class I HDAC2, and the impact of class I HDAC inhibition on MYC function.Co-immunoprecipitation and mass spectrometry was used to determine the co-localization of MYC and HDAC2. ChIP-sequencing and gene expression profiling was used to analyze the co- localization of MYC and HDAC2 on DNA and the impact on transcriptional activity in primary tumors and a MYC amplified cell line treated with the class I HDAC inhibitor entinostat. The effect on MYC was investigated by quantitative RT-PCR, Western blot and immunofluorescence.HDAC2 is a cofactor of MYC in MYC amplified medulloblastoma. The MYC-HDAC2 complex is bound to genes defining the MYC-dependent transcriptional profile. Class I HDAC inhibition leads to stabilization and reduced DNA-binding of MYC protein inducing a down-regulation of MYC activated genes (MAGs) and up-regulation of MYC repressed genes (MRGs). MAGs and MRGs are characterized by opposing biological functions and by distinct E-box distribution.Our data elucidates the molecular interaction of MYC and HDAC2 and support a model in which inhibition of class I HDACs directly targets MYC´s trans-activating and trans-repressing function.

Note: #EA:B310#LA:B310#2021 Feb 25;23(2):226-239

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Contributing Institute(s):

1. KKE Pädiatrische Onkologie (B310)
2. DKTK HD zentral (HD01)
3. B062 Pädiatrische Neuroonkologie (B062)
4. DKTK ED ES zentral (ED01)
5. KKE Neuropathologie (B300)
6. B087 Neuroblastom Genomik (B087)
7. B230 Proteomik (B230)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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