CCBE1 promotes mitochondrial fusion by inhibiting the TGF3-DRP1 axis to prevent the progression of hepatocellular carcinoma

The extracellular matrix (ECM), as an important component of the tumor microenvironment, exerts various roles in tumor formation. Mitochondrial dynamic disorder is closely implicated in tumorigenesis, including hyperfission in HCC. We aimed to determine the influence of the ECM-related protein CCBE1 on mito-chondrial dynamics in HCC. Here, we found that CCBE1 was capable of promoting mitochondrial fusion in HCC. Initially, CCBE1 expression was found to be significantly downregulated in tumors compared with nontumor tissues, which resulted from hypermethylation of the CCBE1 promoter in HCC. Further-more, CCBE1 overexpression or treatment with recombinant CCBE1 protein dramatically inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, CCBE1 functioned as an inhibitor of mitochondrial fission by preventing the location of DRP1 on mitochondria through inhibiting its phosphorylation at Ser616 by directly binding with TGF3R2 to inhibit TGF3 signaling activity. In addi-tion, a higher percentage of specimens with higher DRP1 phosphorylation was present in patients with lower CCBE1 expression than in patients with higher CCBE1 expression, which further confirmed the inhibitory effect of CCBE1 on DRP1 phosphorylation at Ser616. Collectively, our study highlights the crucial roles of CCBE1 in mitochondrial homeostasis, suggesting strong evidence for this process as a potential therapeutic strategy for HCC.(c) 2023 Elsevier B.V. All rights reserved.

Automated summary

This study found that the extracellular matrix-related protein CCBE1 promotes mitochondrial fusion in hepatocellular carcinoma (HCC) and inhibits mitochondrial fission by preventing the localization of DRP1 on mitochondria through inhibiting its phosphorylation at Ser616 by directly binding with TGF3R2 to inhibit TGF3 signaling activity. Increased CCBE1 expression or treatment with recombinant CCBE1 protein significantly inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo, suggesting CCBE1 as a potential therapeutic strategy for HCC.