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

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.

Reviewing Editor

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

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.

Version 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.

Metrics

  • 3,905
    views
  • 431
    downloads
  • 24
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2017)
FXR1 regulates transcription and is required for tumor growth in TP53 homozygous deletion human cancers
eLife 6:e26129.
https://doi.org/10.7554/eLife.26129

Share this article

https://doi.org/10.7554/eLife.26129

Further reading

    1. Cancer Biology
    2. Genetics and Genomics
    Jose Mario Bello Pineda, Robert K Bradley
    Research Article

    Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10–50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

    1. Cancer Biology
    2. Cell Biology
    Helmut Bischof, Selina Maier ... Robert Lukowski
    Research Article

    Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the ‘Warburg effect’, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.