FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer.

Abstract

RNASET2 (Ribonuclease T2) functions as a tumor suppressor in preventing ovarian tumorigenesis. However, the mechanisms underlying the regulation of RNASET2 protein are completely unknown. Here we identified the F-box protein FBXO6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin E3 ligase for RNASET2. We found that the interaction between FBXO6 and RNASET2 induced RNASET2 instability through the ubiquitin-mediated proteasome degradation pathway. FBXO6 promoted K48-dependent ubiquitination of RNASET2 via its FBA domain. Through analysis of the TCGA dataset, we found that FBXO6 was significantly increased in ovarian cancer tissues and the high expression of FBXO6 was related to the poor overall survival (OS) of ovarian cancer patients at advanced stages. An inverse correlation between the protein levels of FBXO6 and RNASET2 was observed in clinic ovarian cancer samples. Depletion of FBXO6 promoted ovarian cancer cells proliferation, migration, and invasion, which could be partially reversed by RNASET2 silencing. Thus, our data revealed a novel FBXO6-RNASET2 axis, which might contribute to the development of ovarian cancer. We propose that inhibition of FBXO6 might represent an effective therapeutic strategy for ovarian cancer treatment.

• Authors: Mei Ji, Zhao Zhao, Yue Li, Penglin Xu, Jia Shi, Zhe Li, Kaige Wang, Xiaotian Huang, Bin Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 4 Pg. 317 (03 25 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33767133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cullin 1
• Cullin Proteins
• Tumor Suppressor Proteins
• FBXO6 protein, human
• SKP Cullin F-Box Protein Ligases
• Ribonucleases
• RNASET2 protein, human

Topics

• Animals
• Cell Line, Tumor
• Cullin Proteins (metabolism)
• Female
• HEK293 Cells
• Heterografts
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Ribonucleases (genetics, metabolism)
• SKP Cullin F-Box Protein Ligases (genetics, metabolism)
• Transfection
• Tumor Suppressor Proteins (genetics, metabolism)
• Ubiquitination