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Abstract
BackgroundGermline mutations in a tumor suppressor gene FLCN lead to development of fibrofolliculomas, lung cysts and renal cell carcinoma (RCC) in Birt-Hogg-Dubé syndrome. TFE3 is a member of the MiTF/TFE transcription factor family and Xp11.2 translocations found in sporadic RCC involving TFE3 result in gene fusions and overexpression of chimeric fusion proteins that retain the C-terminal DNA binding domain of TFE3. We found that GPNMB expression, which is regulated by MiTF, was greatly elevated in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Since TFE3 is implicated in RCC, we hypothesized that elevated GPNMB expression was due to increased TFE3 activity resulting from the inactivation of FLCN.Methodology/Principal FindingsTFE3 knockdown reduced GPNMB expression in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Moreover, FLCN knockdown induced GPNMB expression in FLCN-restored renal cancer cells. Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization as revealed by elevated GPNMB mRNA and protein expression, and predominantly nuclear immunostaining of TFE3 in renal cancer cells, mouse embryo fibroblast cells, mouse kidneys and mouse and human renal tumors. Nuclear localization of TFE3 was associated with TFE3 post-translational modifications including decreased phosphorylation.Conclusions/SignificanceIncreased TFE3 activity is a downstream event induced by FLCN inactivation and is likely to be important for renal tumor development. This study provides an important novel mechanism for induction of TFE3 activity in addition to TFE3 overexpression resulting from Xp11.2 translocations, suggesting that TFE3 may be more broadly involved in tumorigenesis.
Highlights
Genetic studies have revealed several tumor suppressor genes [von hippel lindau (VHL), fumarate hydratase (FH), succinate dehydrogenase subunit B (SDHB) and folliculin (FLCN)] and proto-oncogenes that are responsible for the development of renal cell carcinoma (RCC) [1]
We examined whether microphthalmia transcription factor (MiTF) and TFE3 transcription factor expressions were correlated with GPNMB expression (Fig. 1B)
GPNMB expression was high in the UOK146 cell line (Fig. 1B) that was established from a sporadic kidney tumor harboring a chromosomal translocation, t(X;1)(p11.2;q21), which expressed a high level of the resulting gene fusion product, PRCC-TFE3 [5]
Summary
Genetic studies have revealed several tumor suppressor genes [von hippel lindau (VHL), fumarate hydratase (FH), succinate dehydrogenase subunit B (SDHB) and folliculin (FLCN)] and proto-oncogenes (hepatocyte growth factor receptor MET) that are responsible for the development of renal cell carcinoma (RCC) [1]. MiTF/TFE transcription factor family, are highly expressed in the nucleus as a result of chromosomal translocations and are responsible for the development of juvenile renal cancer [5,6]. Germline mutations in a tumor suppressor gene FLCN lead to development of fibrofolliculomas, lung cysts and renal cell carcinoma (RCC) in Birt-Hogg-Dubesyndrome. TFE3 is a member of the MiTF/TFE transcription factor family and Xp11.2 translocations found in sporadic RCC involving TFE3 result in gene fusions and overexpression of chimeric fusion proteins that retain the C-terminal DNA binding domain of TFE3. We found that GPNMB expression, which is regulated by MiTF, was greatly elevated in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Since TFE3 is implicated in RCC, we hypothesized that elevated GPNMB expression was due to increased TFE3 activity resulting from the inactivation of FLCN
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