IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v5y2014i1d10.1038_ncomms6165.html
   My bibliography  Save this article

Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

Author

Listed:
  • Michael V. Gormally

    (University Chemical Laboratory, University of Cambridge
    Cancer Research UK, Li Ka Shing Centre, Cambridge Institute
    National Center for Advancing Translational Sciences, NIH)

  • Thomas S. Dexheimer

    (National Center for Advancing Translational Sciences, NIH)

  • Giovanni Marsico

    (Cancer Research UK, Li Ka Shing Centre, Cambridge Institute)

  • Deborah A. Sanders

    (Cancer Research UK, Li Ka Shing Centre, Cambridge Institute)

  • Christopher Lowe

    (University Chemical Laboratory, University of Cambridge)

  • Dijana Matak-Vinković

    (University Chemical Laboratory, University of Cambridge)

  • Sam Michael

    (National Center for Advancing Translational Sciences, NIH)

  • Ajit Jadhav

    (National Center for Advancing Translational Sciences, NIH)

  • Ganesha Rai

    (National Center for Advancing Translational Sciences, NIH)

  • David J. Maloney

    (National Center for Advancing Translational Sciences, NIH)

  • Anton Simeonov

    (National Center for Advancing Translational Sciences, NIH)

  • Shankar Balasubramanian

    (University Chemical Laboratory, University of Cambridge
    Cancer Research UK, Li Ka Shing Centre, Cambridge Institute)

Abstract

The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA-binding domain (DBD) and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Here—from a high-throughput screen applied to a library of 54,211 small molecules—we identify novel small molecule inhibitors of FOXM1 that block DNA binding. One of the identified compounds, FDI-6 (NCGC00099374), is characterized in depth and is shown to bind directly to FOXM1 protein, to displace FOXM1 from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional downregulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically downregulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-PCR. This small molecule-mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors.

Suggested Citation

  • Michael V. Gormally & Thomas S. Dexheimer & Giovanni Marsico & Deborah A. Sanders & Christopher Lowe & Dijana Matak-Vinković & Sam Michael & Ajit Jadhav & Ganesha Rai & David J. Maloney & Anton Simeon, 2014. "Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6165
    DOI: 10.1038/ncomms6165
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms6165
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms6165?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Hue M. La & Jinyue Liao & Julien M. D. Legrand & Fernando J. Rossello & Ai-Leen Chan & Vijesh Vaghjiani & Jason E. Cain & Antonella Papa & Tin Lap Lee & Robin M. Hobbs, 2022. "Distinctive molecular features of regenerative stem cells in the damaged male germline," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Bing Yang & Liqing Lu & Ting Xiong & Wei Fan & Jiaohong Wang & Lucía Barbier-Torres & Jyoti Chhimwal & Sonal Sinha & Takashi Tsuchiya & Nirmala Mavila & Maria Lauda Tomasi & DuoYao Cao & Jing Zhang & , 2024. "The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6165. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.