CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma

• Published in: Cancer science Vol. 113; no. 1; pp. 91 - 108
• Main Authors: Zhang, Encheng, Chen, Siteng, Tang, Heting, Fei, Cheng, Yuan, Zhihao, Mu, Xingyu, Qin, Yan, Liu, Haixia, Fan, Yu, Tan, Mingyue, Wang, Xiang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-01-2022; John Wiley and Sons Inc
• Subjects: Amino Acid Motifs; Animals; Antibodies; Antigens; Biomarkers, Tumor - chemistry; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; CDC2 Protein Kinase - metabolism; Cdc4 protein; CDK1; Cell adhesion & migration; Cell Line, Tumor; Clear cell-type renal cell carcinoma; Degradation; Disease Progression; F-Box-WD Repeat-Containing Protein 7 - metabolism; FBXW7; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Liver cancer; Male; Membranes; Metastasis; Mice; mTOR Associated Protein, LST8 Homolog - chemistry; mTOR Associated Protein, LST8 Homolog - genetics; mTOR Associated Protein, LST8 Homolog - metabolism; Neoplasm Metastasis; Neoplasm Transplantation; Original; Pancreatic cancer; Peptides; Phosphorylation; Proteasomes; protein degradation; Proteins; Proteolysis; renal cell carcinoma; Tumor suppressor genes; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Up-Regulation; CDK1; renal cell carcinoma; FBXW7; ubiquitination; protein degradation
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15188

Recent studies have reported that MLST8 is upregulated in many malignant tumors. Nevertheless, the underlying molecular mechanism is still unclear. The aim of this work was to investigate how MLST8 contributes to the development and progression of clear cell renal cell carcinoma (ccRCC). MLST8 is an oncogenic protein in the TCGA database and ccRCC clinical specimens. We also ascertain that MLST8 interacts with FBXW7, which was universally regarded as an E3 ubiquitin ligase. MLST8 can be degraded and ubiquitinated by tumor suppressor FBXW7. FBXW7 recognizes a consensus motif (T/S) PXX (S/T/D/E) of MLST8 and triggers MLST8 degradation via the ubiquitin‐proteasome pathway. Strikingly, the activated cyclin dependent kinase 1 (CDK1) kinase engages in the MLST8 phosphorylation required for FBXW7‐mediated degradation. In vitro, we further prove that MLST8 is an essential mediator of FBXW7 inactivation‐induced tumor growth, migration, and invasion. Furthermore, the MLST8 and FBXW7 proteins are negatively correlated in human renal cancer specimens. Our findings suggest that MLST8 is a putative oncogene that functions via interaction with FBXW7, and inhibition MLST8 could be a potential future target in ccRCC treatment.
Schematic diagram of the CDK1‐FBXW7α signaling axis in the regulation of MLST8 protein degradation.