Open AccessCDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma
Author(s) -
Zhang Encheng,
Chen Siteng,
Tang Heting,
Fei Cheng,
Yuan Zhihao,
Mu Xingyu,
Qin Yan,
Liu Haixia,
Fan Yu,
Tan Mingyue,
Wang Xiang
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15188
Subject(s) - ubiquitin ligase , ubiquitin , cyclin dependent kinase 1 , cancer research , biology , skp2 , oncogene , proteasome , cell cycle , protein degradation , microbiology and biotechnology , downregulation and upregulation , f box protein , cancer , biochemistry , genetics , gene
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.