1. Cancer Biology
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FXR1 regulates transcription and is required for tumor growth in TP53 homozygous deletion human cancers

  1. Yichao Fan
  2. Jiao Yue
  3. Mengtao Xiao
  4. Han Han-Zhang
  5. Yao Vickie Wang
  6. Chun Ma
  7. Zhilin Deng
  8. Yingxiang Li
  9. Yanyan Yu
  10. Xinghao Wang
  11. Shen Niu
  12. Youjia Hua
  13. Zhiping Weng
  14. Peter Atadja
  15. En Li
  16. Bin Xiang  Is a corresponding author
  1. Novartis Institute for BioMedical Research, China
  2. Novartis Institutes for BioMedical Research, China
  3. Tongji University, China
Research Article
  • Cited 11
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Cite this article as: eLife 2017;6:e26129 doi: 10.7554/eLife.26129

Abstract

Tumor suppressor p53 prevents cell transformation by inducing apoptosis and other responses. Homozygous TP53 deletion occurs in various types of human cancers for which no therapeutic strategies have yet been reported. Based on TCGA database analysis, TP53 homozygous deletion locus mostly exhibits co-deletion of the neighboring gene FXR2, which belongs to the Fragile X gene family. Here, we demonstrate that inhibition of the remaining family member FXR1 selectively blocks cell proliferation in cancer cells containing homozygous deletion of both TP53 and FXR2 in a collateral lethality manner. Mechanistically, in addition to its RNA-binding function, FXR1 recruits transcription factor STAT1 or STAT3 to gene promoters at the chromatin interface and regulates transcription thus, at least partially, mediating cell proliferation. Our study anticipates that inhibition of FXR1 is a potential therapeutic approach to targeting human cancers harboring TP53 homozygous deletion.

Article and author information

Author details

  1. Yichao Fan

    Epigenetic Discovery, Novartis Institute for BioMedical Research, Shanghai, China
    Competing interests
    No competing interests declared.
  2. Jiao Yue

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Jiao Yue, Jiao Yue is an employee for Novartis, Inc., where part of the study was conducted..
  3. Mengtao Xiao

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Mengtao Xiao, Mengtao Xiao is an employee for Novartis, Inc., where part of the study was conducted..
  4. Han Han-Zhang

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Han Han-Zhang, Han Han-Zhang is an employee for Novartis, Inc., where part of the study was conducted..
  5. Yao Vickie Wang

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    No competing interests declared.
  6. Chun Ma

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    No competing interests declared.
  7. Zhilin Deng

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    No competing interests declared.
  8. Yingxiang Li

    Department of Bioinformatics, Tongji University, Shanghai, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0835-9280
  9. Yanyan Yu

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Yanyan Yu, Yanyan Yu is an employee for Novartis, Inc., where part of the study was conducted..
  10. Xinghao Wang

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    No competing interests declared.
  11. Shen Niu

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Shen Niu, Shen Niu is an employee for Novartis, Inc., where part of the study was conducted..
  12. Youjia Hua

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Youjia Hua, Youjia Hua is an employee for Novartis, Inc., where part of the study was conducted..
  13. Zhiping Weng

    Department of Bioinformatics, Tongji University, Shanghai, China
    Competing interests
    No competing interests declared.
  14. Peter Atadja

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    Peter Atadja, Peter Atadja is an employee for Novartis, Inc., where part of the study was conducted..
  15. En Li

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    Competing interests
    No competing interests declared.
  16. Bin Xiang

    Epigenetic Discovery, Novartis Institutes for BioMedical Research, Shanghai, China
    For correspondence
    bin.xiang@novartis.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6973-100X

Funding

Novartis (Research)

  • Bin Xiang

Novartis (Postdoc program)

  • Yichao Fan

The authors declare that there was no funding for this work.

Ethics

Animal experimentation: All the procedures related to animal handling, care and the treatment in the study were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). The approved protocol number is R20150728-Mouse and Rat. The animals were daily checked for any effects of tumor growth and treatments on normal behavior such as mobility, food and water consumption, body weight gain/loss, eye/hair matting and any other abnormal effects. Death and observed clinical signs were recorded.

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Publication history

  1. Received: February 17, 2017
  2. Accepted: August 1, 2017
  3. Accepted Manuscript published: August 2, 2017 (version 1)
  4. Accepted Manuscript updated: August 4, 2017 (version 2)
  5. Version of Record published: September 12, 2017 (version 3)

Copyright

© 2017, Fan 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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