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Nuclear translocation of ASPL-TFE3 fusion protein creates favorable metabolism by mediating autophagy in translocation renal cell carcinoma

Abstract

The ASPL-TFE3 fusion gene, resulting from t(X;17)(p11.2;q25.3), is one of the most commonly identified fusion genes in Xp11 translocation renal cell carcinoma (tRCC). However, its roles and underlying mechanism in RCC development are not yet clear. Here, we identified ASPL-TFE3 fusion as the most common tRCC subtype in a Chinese population (29/126, 23.03%). This fusion protein translocated into the nucleus and promoted RCC cell proliferation both in vitro and in vivo. Mechanistically, the fusion protein transcriptionally activated the lysosome-autophagy pathway by binding to the promoters of lysosome-related genes. Autophagy, activated by ASPL-TFE3, enabled RCC cells to escape energy stress by promoting the utilization of proteins and lipids. Moreover, we found that the ASPL-TFE3 fusion escaped regulation by the classic mTOR-TFE3 signal and instead activated phospho-mTOR and its downstream targets. Finally, targeting both autophagy and the mTOR axis resulted in a greater antiproliferative effect than single pathway inhibition. In summary, these results confirmed the ASPL-TFE3 fusion as a master regulator of metabolic adaptation mediated by autophagy in tRCC. The simultaneous manipulation of autophagy and the mTOR axis may represent a novel treatment strategy for ASPL-TFE3 fusion RCC.

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Fig. 1: The TFE3 fusion protein accumulated in the nucleus in ASPL-TFE3 tRCC.
Fig. 2: ASPL-TFE3 enhanced the proliferation, migration, and invasion capacity of RCC cells.
Fig. 3: Transcriptomic analysis of ASPL-TFE3-regulated genes by GeneChip in ACHN cells.
Fig. 4: Constitutive nuclear import of TFE3 controls the autophagy–lysosome pathway in RCC.
Fig. 5: GeneChip and ChIP-seq combined analysis showed transcriptional regulation of lysosome-related genes by ASPL-TFE3.
Fig. 6: ASPL-TFE3 promotes TFE3 nuclear localization independent of the mTOR signaling pathway.
Fig. 7: Effective autophagy/mTOR inhibition in TFE3- or ASPL-TFE3-overexpressing RCC cell lines.
Fig. 8: Graphic abstract.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872095 to QR, 81903385 to YC, 81902836 to YG, and 81802557 to QX), the National Natural Science Foundation of Jiangsu Province (BK20180291 to QX), and Natural Science Foundation of Zhejiang Province (LY21H160052 to MZ).

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Correspondence to Yang Cheng or Yayun Gu or Qiu Rao.

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Fang, R., Wang, X., Xia, Q. et al. Nuclear translocation of ASPL-TFE3 fusion protein creates favorable metabolism by mediating autophagy in translocation renal cell carcinoma. Oncogene 40, 3303–3317 (2021). https://doi.org/10.1038/s41388-021-01776-8

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