FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division

Abstract

Endometrial carcinoma (ECa) is the most common malignant gynecological cancer, with an increased incidence and fatality rate worldwide, while the pathogenesis is still largely unknown. In this study, we confirmed that FBXO7, a gene coding FBXO7 E3 ubiquitin ligase, is significantly downregulated and mutated (5.87%; 31/528) in ECa specimens, and the abnormal low expression and mutations of FBXO7 are associated with the occurrence of ECa. We also identify the excessive expression of INF2 protein, a key factor that triggers mitochondrial division by recruiting the DRP1 protein, and the elevated INF2 protein is significantly negatively correlated with the low FBXO7 protein in ECa specimens. Mechanistically, FBXO7 restrains ECa through inhibiting INF2-associated mitochondrial division via FBXO7-mediated ubiquitination and degradation of INF2. Moreover, we found that ECa-associated FBXO7 mutants are defective in the ubiquitination and degradation of INF2, promoting ECa cells proliferation, migration and apoptosis inhibition via inducing mitochondrial hyper-division. In addition, we found that it could reverse FBXO7 deletion or ECa-associated FBXO7 mutants-induced proliferation, migration, apoptosis inhibition and mitochondrial hyper-division of ECa cells by INF2 or DNM1L knockdown, or DRP1 inhibitor Mdivi-1. In summary, our study shows that FBXO7 acts as a novel tumor suppressor in ECa by inhibiting INF2-DRP1 axis-associated mitochondrial division through the ubiquitination and degradation of INF2 while the effect is destroyed by ECa-associated FBXO7 and INF2 mutants, highlights the key role of FBXO7-INF2-DRP1 axis in ECa tumorigenesis and provides a new viewpoint to treat ECa patients with FBXO7 deletion or mutations by targeting INF2-DRP1 axis-associated mitochondrial division.

Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer

“…On the other hand, the atypical ubiquitination of INF2 by the CRL3 SPOP ubiquitin ligase complex reduces its ER localization and inhibits mitochondrial division [ 32 ]. Moreover, a recent study has identified that F-box protein 7 (FBXO7) induces ubiquitination and degradation of INF2, thereby inhibiting INF2-DRP1 axis-associated mitochondrial fission [ 15 ]. Our findings contribute to the understanding of INF2 post-translational modifications, demonstrating that increased phosphorylation of INF2 Ser1077 in EC cells enhances ER localization, leading to greater recruitment of DRP1 to mitochondria.…”

“…Mdivi-1, which was first identified in 2008, inhibits DRP1 assembly and GTPase activity, thereby inhibiting mitochondrial fission [ 37 ]. Mdivi-1 has demonstrated the ability to inhibit the proliferation and migration of EC cells, possibly by regulating reactive oxygen species in mitochondria [ 15 ]. Given that high INF2 expression enhances EC proliferation by promoting mitochondrial division, inhibition of mitochondrial division may be a viable approach for the treatment of EC.…”

“…It is now widely accepted that mitochondrial fission promotes tumor formation, whereas mitochondrial fusion acts as a suppressor of tumorigenesis [ 9 ]. Numerous studies have demonstrated that an imbalance in mitochondrial dynamics, leading to mitochondrial fragmentation, is associated with tumor development in various cancers such as lung cancer [ 10 ], breast cancer [ 6 ], thyroid cancer [ 11 ], medulloblastoma [ 12 ], liver cancer [ 13 ], and EC [ 14 , 15 ].…”

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

“…INF2 protein in the ER can trigger mitochondrial division by recruiting DRP1 protein, and elevated INF2 has been significantly, negatively correlated with the hypocancerous FBXO7 protein in endometrial cancer specimens ( 98 ). Under energetic stress conditions, AMPK induces phosphorylation of INF2 (Ser1077), leading to its increased localization to the ER, which enhances DRP recruitment to mitochondria and promotes endometrial cancer cell growth ( 99 ).…”

FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma

“…In terms of its SCF-dependent function, FBXO7 interacts with and ubiquitinates specific substrates, thus regulating several cellular processes, including mitophagy 21 , proteasomal assembly 22 , and glycolysis 23 . Recent studies have demonstrated that FBXO7 is deregulated in several cancers, such as lung cancer, colon cancer and endometrial cancer 19 , 24 . However, whether FBXO7 plays a role in HCC remains unclear.…”