HDAC3 functions as a positive regulator in Notch signal transduction

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Abstract

Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.

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Most cited references 59

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Identifying ChIP-seq enrichment using MACS.

Jianxing Feng, Tao Liu, Bo Qin … (2012)

Model-based analysis of ChIP-seq (MACS) is a computational algorithm that identifies genome-wide locations of transcription/chromatin factor binding or histone modification from ChIP-seq data. MACS consists of four steps: removing redundant reads, adjusting read position, calculating peak enrichment and estimating the empirical false discovery rate (FDR). In this protocol, we provide a detailed demonstration of how to install MACS and how to use it to analyze three common types of ChIP-seq data sets with different characteristics: the sequence-specific transcription factor FoxA1, the histone modification mark H3K4me3 with sharp enrichment and the H3K36me3 mark with broad enrichment. We also explain how to interpret and visualize the results of MACS analyses. The algorithm requires ∼3 GB of RAM and 1.5 h of computing time to analyze a ChIP-seq data set containing 30 million reads, an estimate that increases with sequence coverage. MACS is open source and is available from http://liulab.dfci.harvard.edu/MACS/.

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The Varied Roles of Notch in Cancer.

Jon C Aster, Warren Pear, Stephen Blacklow (2017)

Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.

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FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors

Jennifer O'Neil, Jonathan Grim, Peter Strack … (2007)

γ-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.

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Author and article information

Journal

Journal ID (nlm-ta): Nucleic Acids Res

Journal ID (iso-abbrev): Nucleic Acids Res

Journal ID (publisher-id): nar

Title: Nucleic Acids Research

Publisher: Oxford University Press

ISSN (Print): 0305-1048

ISSN (Electronic): 1362-4962

Publication date (Print): 17 April 2020

Publication date (Electronic): 28 February 2020

Publication date PMC-release: 28 February 2020

Volume: 48

Issue: 7

Pages: 3496-3512

Affiliations

[1 ] Institute of Biochemistry, University of Giessen , Friedrichstrasse 24, 35392 Giessen, Germany

[2 ] Institute for Genetics, University of Giessen , Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany

[3 ] Bioinformatics and Systems Biology, University of Giessen , Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany

[4 ] University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine III , Albert-Einstein-Allee 23, 89081 Ulm, Germany

[5 ] Cooperation Unit “Mechanisms of Leukemogenesis’’ (B061), German Cancer Research Center (DKFZ) , Im Neuenheimer Feld 280, 69120 Heidelberg Germany

[6 ] Genomics Core Facility, Institute of Molecular Oncology, Philipps-University , Hans-Meerwein-Str. 3, 35043 Marburg, Germany

[7 ] Rudolf Buchheim Institute of Pharmacology, University of Giessen , Schubertstrasse 81, 35392 Giessen, Germany

[8 ] University Medical Center Ulm, Center for Internal Medicine, Molecular Cardiology, Department of Internal Medicine II , Albert-Einstein-Allee 23, 89081 Ulm, Germany

[9 ] University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I , Albert-Einstein-Allee 23, 89081 Ulm, Germany

Author notes

To whom the correspondence should be addressed. Tel: +49 641 99 47400; Fax: +49 641 9947409; Email: tilman.borggrefe@ 123456biochemie.med.uni-giessen.de

Correspondence may also be addressed to Franz Oswald. Tel: +49 731 50044544; Fax: +49 731 50044502; Email: franz.oswald@ 123456uni-ulm.de

The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.

Author information

Francesca Ferrante http://orcid.org/0000-0003-4325-5452

Article

Publisher ID: gkaa088

DOI: 10.1093/nar/gkaa088

PMC ID: 7144913

PubMed ID: 32107550

SO-VID: 816311ae-24fe-4985-9cf5-e9d6d769876e

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

History

Date accepted : 03 February 2020

Date revision received : 29 January 2020

Date received : 30 April 2019

Page count

Pages: 17

Funding

Funded by: Deutsche Forschungsgemeinschaft, DOI 10.13039/501100001659;

Award ID: Kr1143/7-3

Award ID: KR1143/9-1

Award ID: TRR81/2

Award ID: SFB1021

Award ID: SFB 1074/B02

Award ID: JU 2859/2-1

Funded by: Heisenberg program;

Award ID: BO 1639/5-1

Award ID: SFB 1074/A03

Award ID: OS 287/4-1

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HDAC3 functions as a positive regulator in Notch signal transduction

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Most cited references 59

Identifying ChIP-seq enrichment using MACS.

The Varied Roles of Notch in Cancer.

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors

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