MFN2 suppresses clear cell renal cell carcinoma progression by modulating mitochondria‐dependent dephosphorylation of EGFR

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most lethal renal cancer. An overwhelming increase of patients experience tumor progression and unfavorable prognosis. However, the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear. Therefore, uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC. In this study, we sought to investigate the role of mitofusin‐2 (MFN2) in supressing ccRCC tumorigenesis and metastasis. METHODS: The expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort. Both in vitro and in vivo experiments, including cell proliferation, xenograft mouse models and transgenic mouse model, were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC. RNA‐sequencing, mass spectrum analysis, co‐immunoprecipitation, bio‐layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor‐supressing role of MFN2. RESULTS: we reported a tumor‐suppressing pathway in ccRCC, characterized by mitochondria‐dependent inactivation of epidermal growth factor receptor (EGFR) signaling. This process was mediated by the outer mitochondrial membrane (OMM) protein MFN2. MFN2 was down‐regulated in ccRCC and associated with favorable prognosis of ccRCC patients. in vivo and in vitro assays demonstrated that MFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway. In a kidney‐specific knockout mouse model, loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney. Mechanistically, MFN2 preferably binded small GTPase Rab21 in its GTP‐loading form, which was colocalized with endocytosed EGFR in ccRCC cells. Through this EGFR‐Rab21‐MFN2 interaction, endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM‐residing tyrosine‐protein phosphatase receptor type J (PTPRJ). CONCLUSIONS: Our findings uncover an important non‐canonical mitochondria‐dependent pathway regulating EGFR signaling by the Rab21‐MFN2‐PTPRJ axis, which contributes to the development of novel therapeutic strategies for ccRCC.