EFHD1, a novel mitochondrial regulator of tumor metastasis in clear cell renal cell carcinoma.
Kun MengHu YuyuWang DingkangLi YuyingShi FujinLu JiangliWang YangYun CaoZhang Chris ZhiyiHe Qing-YuPublished in: Cancer science (2023)
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 TCGA and CPTAC 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 2+ , 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 MCU through its N-terminal domain. The interaction of EFHD1 and MCU suppressed the uptake of Ca 2+ 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 Hippo/YAP pathway and serves as a novel regulator in the progression of ccRCC.
Keyphrases
- oxidative stress
- transcription factor
- cell migration
- poor prognosis
- induced apoptosis
- signaling pathway
- cell proliferation
- protein kinase
- cell death
- gene expression
- pi k akt
- dna methylation
- stem cells
- genome wide identification
- electronic health record
- big data
- high resolution
- mesenchymal stem cells
- bioinformatics analysis
- atomic force microscopy