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Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear

Seung-Beom Hong1, HyoungBin Oh, Vladimir A Valera

  • 1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

Plos One
|January 7, 2011
PubMed
Abstract

Insights

FLCN gene inactivation increases TFE3 activity, promoting renal cell carcinoma (RCC) development. This discovery reveals a new mechanism for TFE3 activation in tumorigenesis beyond gene fusions.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Birt-Hogg-Dubé syndrome is linked to FLCN tumor suppressor gene mutations, causing fibrofolliculomas, lung cysts, and renal cell carcinoma (RCC).
  • Xp11.2 translocations in sporadic RCC lead to TFE3 gene fusions and overexpression of chimeric proteins.
  • Elevated GPNMB expression, regulated by MiTF, was observed in renal cancer cells with TFE3 translocations or FLCN inactivation.

Purpose of the Study:

  • To investigate the hypothesis that elevated GPNMB expression in RCC is caused by increased TFE3 activity due to FLCN inactivation.
  • To elucidate the relationship between FLCN, TFE3, and GPNMB expression in renal cancer.

Main Methods:

  • TFE3 and FLCN knockdown experiments in renal cancer cells.
  • Analysis of GPNMB mRNA and protein expression.
  • Immunohistochemical analysis of TFE3 localization and phosphorylation in various cell and tissue types.
  • Comparison of TFE3 activity in FLCN-inactivated versus FLCN-restored cells.

Main Results:

  • TFE3 knockdown decreased GPNMB expression in cells with TFE3 translocations or FLCN inactivation.
  • FLCN knockdown induced GPNMB expression, while wildtype FLCN suppressed it.
  • FLCN inactivation correlated with increased TFE3 transcriptional activity, nuclear localization, and elevated GPNMB expression.
  • Nuclear TFE3 localization was associated with decreased phosphorylation.

Conclusions:

  • Increased TFE3 activity is a downstream consequence of FLCN inactivation and plays a role in renal tumor development.
  • This study identifies a novel mechanism for TFE3 activity induction, broadening its potential involvement in tumorigenesis.
  • TFE3 may be a more significant factor in cancer development than previously recognized, beyond its role in translocation-driven RCC.

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