Abstract
Depletion of kinectin1 (KTN1) provides a potential strategy for inhibiting tumorigenesis of cutaneous squamous cell carcinoma (cSCC) via reduction of epidermal growth factor receptor (EGFR) protein levels. Yet, the underlying mechanisms of KTN1 remain obscure. In this study, we demonstrate that KTN1 knockdown induces EGFR degradation in cSCC cells by promoting the ubiquitin-proteasome system, and that this effect is tumor cell-specific. KTN1 knockdown increases the expression of CCDC40, PSMA1, and ADRM1 to mediate tumor suppressor functions in vivo and in vitro. Mechanistically, c-Myc directly binds to the promoter region of CCDC40 to trigger the CCDC40-ADRM1-UCH37 axis and promote EGFR deubiquitination. Furthermore, KTN1 depletion accelerates EGFR degradation by strengthening the competitive interaction between PSMA1 and ADRM1 to inhibit KTN1/ADRM1 interaction at residues Met1-Ala252. These results are supported by studies in mouse xenografts and human patient samples. Collectively, our findings provide novel mechanistic insight into KTN1 regulation of EGFR degradation in cSCC.
Highlights
The ubiquitin-proteasome system (UPS) consists of two coupled pathways: ubiquitination and proteolysis
KTN1 knockdown reduces epidermal growth factor receptor (EGFR) protein expression postwith siKTN1 compared to siNC in A431 cells; upon transcriptionally and increases apoptosis to repress the cutaneous squamous cell carcinoma (cSCC) cell survival In our previous study, we demonstrated that KTN1 is highly
To directly determine whether EGFR is polyubiquitiny- to investigate whether knockdown UCHL5 may increase EGFR lated in siKTN1-transfected cells, we performed Co-IP assays, stability and ubiquitination, we transfected 2 UCH37 targeted which revealed that polyubiquitin co-immunoprecipitates with siRNAs to knockdown of UCH37 in A431, the results revealed that EGFR
Summary
The ubiquitin-proteasome system (UPS) consists of two coupled pathways: ubiquitination and proteolysis. The EGFR protein levels still decreased significantly at 12 and 18 h after transfection in the siKTN1 + CHX group as compared to the siNC + CHX group in which changes in the UPS caused by KTN1 depletion lead to (Fig. S1C, D, G). These results rule out the possibility that. To further determine whether EGFR protein reduction after siKTN1 transfection is explained by effects on protein degradation, we applied MG132 after siRNA transfection to inhibit proteasomal
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