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Title: | TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas | Authors: | Yin, XQ Wang, B Gan, WD Zhuang, WY Xiang, Z Han, XD Li, DM |
Issue Date: | 2019 | Source: | Journal of experimental and clinical cancer research, 8 Mar. 2019, v. 38, 119, p. 1-16 | Abstract: | Background: Xp11.2 translocation renal cell carcinoma (tRCC) is mainly caused by translocation of the TFE3 gene located on chromosome Xp11.2 and is characterized by overexpression of the TFE3 fusion gene. Patients are diagnosed with tRCC usually before 45years of age with poor prognosis. We investigated this disease using two tRCC cell lines, UOK109 and UOK120, in this study. Methods: The purpose of this study was to investigate the pathogenic mechanism of TFE3 fusions in tRCC based on its subcellular localization, nuclear translocation and transcriptional activity. The expression of TFE3 fusions and other related genes were analyzed by quantitative reverse transcription PCR (qRT-PCR) and Western blot. The subcellular localization of TFE3 was determined using immunofluorescence. The transcriptional activity of TFE3 fusions was measured using a luciferase reporter assay and ChIP analysis. In some experiments, TFE3 fusions were depleted by RNAi or gene knockdown. The TFE3 fusion segments were cloned into a plasmid expression system for expression in cells. Results: Our results demonstrated that TFE3 fusions were overexpressed in tRCC with a strong nuclear retention irrespective of treatment with an mTORC1 inhibitor or not. TFE3 fusions lost its co-localization with lysosomal proteins and decreased its interaction with the chaperone 14-3-3 proteins in UOK109 and UOK120 cells. However, the fusion segments of TFE3 could not translocate to the nucleus and inhibition of Gsk3 could increase the cytoplasmic retention of TFE3 fusions. Both the luciferase reporter assay and ChIP analysis demonstrated that TFE3 fusions could bind to the promoters of the target genes as a wild-type TFE3 protein. Knockdown of TFE3 results in decreased expression of those genes responsible for lysosomal biogenesis and other target genes. The ChIP-seq data further verified that, in addition to lysosomal genes, TFE3 fusions could regulate genes involved in cellular responses to hypoxic stress and transcription. Conclusions: Our results indicated that the overexpressed TFE3 fusions were capable of escaping from the control by the mTOR signaling pathway and were accumulated in the nucleus in UOK109 and UOK120 cells. The nuclear retention of TFE3 fusions promoted the expression of lysosomal genes and other target genes, facilitating cancer cell resistance against an extreme environment. |
Keywords: | TFE3 MTOR Subcellular localization Nuclear retention Lysosome Transcription factor |
Publisher: | BioMed Central | Journal: | Journal of experimental and clinical cancer research | EISSN: | 1756-9966 | DOI: | 10.1186/s13046-019-1101-7 | Rights: | © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The following publication Yin, X. Q., Wang, B., Gan, W. D., Zhuang, W. Y., Xiang, Z., Han, X. D., & Li, D. M. (2019). TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11. 2 translocation renal cell carcinomas. Journal of Experimental & Clinical Cancer Research, 38(1), 119, 1-16 is available at https://dx.doi.org/10.1186/s13046-019-1101-7 |
Appears in Collections: | Journal/Magazine Article |
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Yin_TFE3_Escape_MTOR.pdf | 5.63 MB | Adobe PDF | View/Open |
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