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Research
Gaosong Wu
Wuhan University Zhongnan Hospital
Corresponding Author
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Background
Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC.
Methods
Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP.
Results
TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy. The effects induced by TRIM11 depletion could be rescued by further YAP overexpression. Depletion TRIM11 decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Immuno-precipitation assay shows that TRIM11 associates with YAP, promoting YAP stabilization possibly via inducing YAP mono-ubiquitination. Further mechanistic analysis indicates that the RING domain of TRIM11 interacts with the WW domain of YAP and promotes its mono-ubiquitination, thus prolongs YAP protein half.
Conclusions
Our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 could be a promising therapeutic method for ATC treatment.
Keywords
anaplastic thyroid cancer, TRIM11, YAP, stabilization, mono-ubiquitination
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This is a preprint. It has not completed peer review.
Research
Gaosong Wu
Wuhan University Zhongnan Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 10 Jul, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC.
Methods
Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP.
Results
TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy. The effects induced by TRIM11 depletion could be rescued by further YAP overexpression. Depletion TRIM11 decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Immuno-precipitation assay shows that TRIM11 associates with YAP, promoting YAP stabilization possibly via inducing YAP mono-ubiquitination. Further mechanistic analysis indicates that the RING domain of TRIM11 interacts with the WW domain of YAP and promotes its mono-ubiquitination, thus prolongs YAP protein half.
Conclusions
Our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 could be a promising therapeutic method for ATC treatment.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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