MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
The First Affiliated Hospital of Jinan University, Guangzhou, China.
Cancer Sci. 2023 May;114(5):2029-2040. doi: 10.1111/cas.15749. Epub 2023 Feb 26.
The biological function of many mitochondrial proteins in mechanistic detail has not been well investigated in clear cell renal cell carcinoma (ccRCC). A seven-mitochondrial-gene signature was generated by Lasso regression analysis to improve the prediction of prognosis of patients with ccRCC, using The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium cohort. Among those seven genes, EFHD1 is less studied and its role in the progression of ccRCC remains unknown. The decreased expression of EFHD1 was validated in clinical samples and was correlated with unfavorable outcome. Overexpression of EFHD1 in ccRCC cells resulted in the reduction of mitochondrial Ca , and the inhibition of cell migration and invasion in vitro and tumor metastasis in vivo. Mechanistically, EFHD1 physically bound to the core mitochondrial calcium transporter (mitochondrial calcium uniporter, MCU) through its N-terminal domain. The interaction between EFHD1 and MCU suppressed the uptake of Ca into mitochondria, and deactivated the Hippo/YAP signaling pathway. Further data revealed that the ectopic expression of EFHD1 upregulated STARD13 to enhance the phosphorylation of YAP protein at Ser-127. The knockdown of STARD13 or the overexpression of MCU partly abrogated the EFHD1-mediated induction of phosphorylation of YAP at Ser-127 and suppression of cell migration. Taken together, the newly identified EFHD1-MCU-STARD13 axis participates in the modulation of the Hippo/YAP pathway and serves as a novel regulator in the progression of ccRCC.
许多线粒体蛋白在机制细节上的生物学功能在透明细胞肾细胞癌（ccRCC）中尚未得到很好的研究。通过 Lasso 回归分析生成了一个由七个线粒体基因组成的特征，以改善对 TCGA 和临床蛋白质组肿瘤分析联盟队列中 ccRCC 患者预后的预测。在这七个基因中，EFHD1 研究较少，其在 ccRCC 进展中的作用尚不清楚。EFHD1 的表达减少在临床样本中得到验证，并与不良预后相关。在 ccRCC 细胞中过表达 EFHD1 导致线粒体 Ca 减少，体外细胞迁移和侵袭以及体内肿瘤转移受到抑制。在机制上，EFHD1 通过其 N 端结构域与核心线粒体钙转运体（线粒体钙单向转运蛋白，MCU）物理结合。EFHD1 与 MCU 之间的相互作用抑制了 Ca 进入线粒体，使 Hippo/YAP 信号通路失活。进一步的数据显示，EFHD1 的异位表达上调了 STARD13，以增强 YAP 蛋白在 Ser-127 处的磷酸化。STARD13 的敲低或 MCU 的过表达部分消除了 EFHD1 介导的 YAP 蛋白在 Ser-127 处磷酸化的诱导和细胞迁移的抑制。总之，新鉴定的 EFHD1-MCU-STARD13 轴参与了 Hippo/YAP 通路的调节，是 ccRCC 进展中的一个新调节因子。
