American Association for Cancer Research
Browse

Supplemental Figures S1-4 from Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins

Download (1.87 MB)
journal contribution
posted on 2023-03-30, 23:46 authored by Lisa M. Nilsson, Lydia C. Green, Somsundar Veppil Muralidharan, Dağsu Demir, Martin Welin, Joydeep Bhadury, Derek T. Logan, Björn Walse, Jonas A. Nilsson

Figure S1: Molecular modelling and structure determination by X ray crystallography. Expanded data related to Figure 1B. Figure S2-S3: Ingenuity Pathway analyses of microarray data. Expanded analyses related to Figure 4 and Supplemental dataset 1. Figure S4: Gene-set enrichment analyses of microarray data. Expanded analyses related to Figure 4 and Supplemental dataset 1.

Funding

Swedish Cancer Society

the Swedish Research Council

BioCARE Strategic Grants for Cancer Research

the Knut & Alice Wallenberg Foundation

Assar Gabrielsson Foundation Wilhelm & Martina Lundgren's foundation and Sahlgrenska University Hospita

Maj Bülow Foundation and Göteborgs Läkaresällskap

History

ARTICLE ABSTRACT

Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. Cancer Res; 76(8); 2376–83. ©2016 AACR.

Usage metrics

    Cancer Research

    Categories

    Keywords

    Biological Agents & TherapiesGene therapyDrug Discovery TechnologiesStructural studiesGene RegulationOncogenic transcription factorsGenome BiologySilencing and reactivation of gene expressionStructural genomicsHematological CancersLeukemiasMyelomasOncogenes & Tumor SuppressorsPreclinical ModelsAnimal models of cancerSmall Molecule Agents

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC