Nuclear translocation of ASPL-TFE3 fusion protein creates favorable metabolism by mediating autophagy in translocation renal cell carcinoma
Nuclear translocation of ASPL-TFE3 fusion protein creates favorable metabolism by mediating autophagy in translocation renal cell carcinoma
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ASPL-TFE3融合蛋白的核转位通过介导易位肾细胞癌的自噬创造有利的代谢
DOI：
10.1038/s41388-021-01776-8
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发表时间：
2021-04-12
期刊：
影响因子：
8
通讯作者：
Rao, Qiu
中科院分区：
文献类型：
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作者：
Fang, Ru;Wang, Xiaotong;Rao, Qiu
ASPL-TFE 3融合基因是由t（X;17）（p11.2;q25.3）引起的，是Xp 11易位肾细胞癌（tRCC）中最常见的融合基因之一。然而，其在RCC发展中的作用和潜在机制尚不清楚。在此，我们确定ASPL-TFE 3融合是中国人群中最常见的tRCC亚型（29/126，23.03%）。该融合蛋白在体外和体内均能转位到细胞核内，促进RCC细胞增殖。从机制上讲，融合蛋白通过与溶酶体相关基因的启动子结合来转录激活溶酶体自噬途径。ASPL-TFE 3激活的自噬使RCC细胞通过促进蛋白质和脂质的利用来逃避能量应激。此外，我们发现ASPL-TFE 3融合逃避了经典mTOR-TFE 3信号的调节，而是激活了磷酸化mTOR及其下游靶标。最后，靶向自噬和mTOR轴导致比单一途径抑制更大的抗增殖作用。总之，这些结果证实了ASPL-TFE 3融合物作为tRCC中由自噬介导的代谢适应的主要调节物。自噬和mTOR轴的同时操作可能代表ASPL-TFE 3融合RCC的新治疗策略。
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.