1. Cancer Biology
  2. Chromosomes and Gene Expression
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TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex

  1. Nicole Merritt
  2. Keith Garcia
  3. Dushyandi Rajendran
  4. Zhen-Yuan Lin
  5. Xiaomeng Zhang
  6. Katrina M Mitchell
  7. Nicholas Borcherding
  8. Colleen Fullenkamp
  9. Michael S Chimenti
  10. Anne-Claude Gingras
  11. Kieran F Harvey
  12. Munir R Tanas  Is a corresponding author
  1. University of Iowa, United States
  2. Mount Sinai Hospital, Canada
  3. Peter MacCallum Cancer Centre, Australia
  4. Washington University, United States
  5. Lunenfeld-Tanenbaum Research Institute, Canada
Research Article
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Cite this article as: eLife 2021;10:e62857 doi: 10.7554/eLife.62857
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Abstract

Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers.

Data availability

The accession number for the RNA-Seq data reported in this paper for NIH 3T3 cells is GEO: GSE152736. The accession number for the RNA-Seq data reported in this paper for SW872 cells is GEO: GSE152737. The accession number for the ChIP-Seq data reported in this paper is GEO: GSE152778. The accession number for the ATAC-Seq data reported in this paper is GEO: GSE152733. The accession number for the H3K27ac ChIP-Seq data reported in this paper is GEO: GSE168201. The accession number for the RNA-Seq data after YEATS2 and ZZZ3 knock-down is GEO: GSE168205.

The following data sets were generated

Article and author information

Author details

  1. Nicole Merritt

    Pathology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Keith Garcia

    Pathology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Dushyandi Rajendran

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhen-Yuan Lin

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiaomeng Zhang

    Peter MacCallum Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Katrina M Mitchell

    Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Nicholas Borcherding

    Department of Pathology and Immunology, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Colleen Fullenkamp

    Pathology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael S Chimenti

    Iowa Institute of Human Genetics, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Anne-Claude Gingras

    Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6090-4437
  11. Kieran F Harvey

    Organogenesis and Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Munir R Tanas

    Pathology, University of Iowa, Iowa City, United States
    For correspondence
    munir-tanas@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6779-2642

Funding

Veterans Health Administration Merit Review Program (1 I01 BX003644-01)

  • Munir R Tanas

National Institutes of Health (R01 CA237031-01A1)

  • Munir R Tanas

National Health and Medical Research Council (APP1078220)

  • Kieran F Harvey

Canadian Institutes of Health Research (FDN 144301)

  • Anne-Claude Gingras

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (#9052228-008 ) of the University of Iowa. All injections for mouse xenograft experiments were performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado Anschutz Medical Campus, United States

Publication history

  1. Received: September 7, 2020
  2. Accepted: April 28, 2021
  3. Accepted Manuscript published: April 29, 2021 (version 1)

Copyright

© 2021, Merritt et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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