Nishizawa Hidekazu, Funasaki Shintaro, Ma Wenjuan, Kubota Yoshiaki, Watanabe Kazuhide, Arima Yuichiro, Kuroda Shoichiro, Ito Takaaki, Furuya Mitsuko, Motoshima Takanobu, Nishiyama Akira, Mehanna Sally, Satou Yorifumi, Hasumi Hisashi, Jikuya Ryosuke, Makiyama Kazuhide, Tamura Tomohiko, Oike Yuichi, Tanaka Yasuhito, Suda Toshio, Schmidt Laura S, Linehan W Marston, Baba Masaya, Kamba Tomomi
Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto, Japan.
Genes Cells. 2025 Jan;30(1):e13195. doi: 10.1111/gtc.13195.
Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC.
肿瘤的发展通常需要细胞适应独特的高代谢状态；然而，驱动TFE3重排肾细胞癌（TFE3-RCC）发生这种代谢变化的分子机制仍知之甚少。TFE3-RCC是肾细胞癌的一种罕见亚型，由涉及转录因子TFE3的嵌合蛋白形成所定义。在本研究中，我们分析了细胞系和基因工程小鼠，证明嵌合蛋白PRCC-TFE3的表达通过转录上调HIF1α和HIF2α诱导了缺氧相关特征。PRCC-TFE3对HIF1α的上调通过增强糖酵解导致细胞ATP生成增加，这也为三羧酸循环提供底物，同时维持线粒体氧化磷酸化。我们将TFE3-RCC小鼠模型与Hif1α和/或Hif2α基因敲除小鼠杂交，发现Hif1α而非Hif2α对体内肿瘤发展至关重要。对这些小鼠肾组织的RNA测序和代谢组学分析表明，酮体生成与肿瘤发展呈负相关，而在TFE3-RCC中，从头脂质合成通过HIF1α/SREBP1依赖性机制上调。我们的数据表明，通过PRCC-TFE3/HIF1α/SREBP1轴的协同代谢转变是PRCC-TFE3增强癌细胞代谢、促进TFE3-RCC肿瘤发展的关键机制。
