Abstract

Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown. Here we show that deleting FLCN activates TFE3, upregulating its downstream E-box genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, deletion of FLCN or its binding partners FNIP1/FNIP2 also induces interferon response genes, but independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.

Data availability

Data files of transcriptomic and proteomic data are provided as supplementary table 1. Raw data files deposited on Dryad Digital Repository (RNAseq): doi:10.5061/dryad.6djh9w0zsProteomeXchange (Mass Spec) under accession number PXD021346

The following data sets were generated

Article and author information

Author details

  1. Iris E Glykofridis

    Clinical Genetics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    For correspondence
    i.glykofridis@amsterdamumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1829-2403
  2. Jaco C Knol

    Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Jesper A Balk

    Clinical Genetics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Denise Westland

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Thang V Pham

    Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Sander R Piersma

    Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Sinéad M Lougheed

    Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Sepide Derakhshan

    Oncode Institute, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Puck Veen

    Clinical Genetics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Martin A Rooimans

    Clinical Genetics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Saskia E van Mil

    Clinical Genetics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Franziska Böttger

    Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  13. Pino J Poddighe

    Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  14. Irma van de Beek

    Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  15. Jarno Drost

    Oncode Institute, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  16. Fried JT Zwartkruis

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  17. Renee X de Menezes

    Biostatistics Unit, NKI-AvL, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  18. Hanne EJ Meijers-Heijboer

    Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  19. Arjan C Houweling

    Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  20. Connie R Jimenez

    Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    For correspondence
    c.jimenez@amsterdamumc.nl
    Competing interests
    The authors declare that no competing interests exist.
  21. Rob MF Wolthuis

    Clinical Genetics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
    For correspondence
    r.wolthuis@amsterdamumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3109-1588

Funding

KWF Kankerbestrijding/Alpe d'Huzes Bas Mulder Award

  • Jarno Drost

Foundation Children Cancer Free (Core Funding)

  • Sepide Derakhshan

Oncode Institute

  • Jarno Drost

Cancer Center Amsterdam (CCA2018-5-51)

  • Iris E Glykofridis
  • Rob MF Wolthuis

Cancer Center Amsterdam (Core Funding Mass Spectrometry Infrastructure)

  • Jaco C Knol
  • Thang V Pham
  • Sander R Piersma
  • Connie R Jimenez

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

Reviewing Editor

  1. Wilbert Zwart, Netherlands Cancer Institute, Netherlands

Ethics

Human subjects: BHD T1 and BHD T2 tumor samples were obtained with informed consent. Both tissues are leftover material from surgery and are stored in our BHD biobank (2019.359 at AmsterdamUMC).

Version history

  1. Received: July 31, 2020
  2. Accepted: January 16, 2021
  3. Accepted Manuscript published: January 18, 2021 (version 1)
  4. Version of Record published: February 22, 2021 (version 2)

Copyright

© 2021, Glykofridis 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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  1. Iris E Glykofridis
  2. Jaco C Knol
  3. Jesper A Balk
  4. Denise Westland
  5. Thang V Pham
  6. Sander R Piersma
  7. Sinéad M Lougheed
  8. Sepide Derakhshan
  9. Puck Veen
  10. Martin A Rooimans
  11. Saskia E van Mil
  12. Franziska Böttger
  13. Pino J Poddighe
  14. Irma van de Beek
  15. Jarno Drost
  16. Fried JT Zwartkruis
  17. Renee X de Menezes
  18. Hanne EJ Meijers-Heijboer
  19. Arjan C Houweling
  20. Connie R Jimenez
  21. Rob MF Wolthuis
(2021)
Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells
eLife 10:e61630.
https://doi.org/10.7554/eLife.61630

Share this article

https://doi.org/10.7554/eLife.61630

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