FBXO16-mediated hnRNPL ubiquitination and degradation plays a tumor suppressor role in ovarian cancer.

Abstract

Heterogeneous nuclear ribonucleoprotein L (hnRNPL) is a type of RNA binding protein that highly expressed in a variety of tumors and plays a vital role in tumor progression. However, its post-translational regulation through ubiquitin-mediated proteolysis and the cellular mechanism responsible for its proteasomal degradation remains unclear. F-box proteins (FBPs) function as the substrate recognition subunits of SCF ubiquitin ligase complexes and directly bind to substrates. The aberrant expression or mutation of FBPs will lead to the accumulation of its substrate proteins that often involved in tumorigenesis. Here we discover FBXO16, an E3 ubiquitin ligase, to be a tumor suppressor in ovarian cancer, and patients with the relatively high expression level of FBXO16 have a better prognosis. Silencing or depleting FBXO16 significantly enhanced ovarian cancer cell proliferation, clonogenic survival, and cell invasion by activating multiple oncogenic pathways. This function requires the F-box domain of FBXO16, through which FBXO16 assembles a canonical SCF ubiquitin ligase complex that constitutively targets hnRNPL for degradation. Depletion of hnRNPL is sufficient to inactive multiple oncogenic signaling regulated by FBXO16 and prevent the malignant behavior of ovarian cancer cells caused by FBXO16 deficiency. FBXO16 interacted with the RRM3 domain of hnRNPL via its C-terminal region to trigger the proteasomal degradation of hnRNPL. Failure to degrade hnRNPL promoted ovarian cancer cell proliferation in vitro and tumor growth vivo, phenocopying the deficiency of FBXO16 in ovarian cancer.

• Authors: Mei Ji, Zhao Zhao, Yue Li, Penglin Xu, Jia Shi, Zhe Li, Kaige Wang, Xiaotian Huang, Jing Ji, Wei Liu, Bin Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 8 Pg. 758 (07 31 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34333526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• F-Box Proteins
• FBXO16 protein, human
• Heterogeneous-Nuclear Ribonucleoprotein L
• Tumor Suppressor Proteins

Topics

• Animals
• Carcinogenesis (genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Down-Regulation (genetics)
• F-Box Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Heterogeneous-Nuclear Ribonucleoprotein L (metabolism)
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (metabolism)
• Prognosis
• Protein Binding
• Protein Interaction Maps (genetics)
• Proteolysis
• Tumor Suppressor Proteins (metabolism)
• Ubiquitination