DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation
Autor: | Maoxiao Feng, Guangwei Wei, Haoran Cui, Zhongxi Zhao, Yunshan Wang, Zhenchuan Lei, Qin Wang |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research Proteasome Endopeptidase Complex Tumor suppressor gene Apoptosis medicine.disease_cause lcsh:RC254-282 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine Cell Movement Cell Line Tumor Neoplasms medicine Animals Humans Ubiquitins Cell Proliferation Matrigel biology PDCD4 Chemistry Research Ubiquitination Cancer Computational Biology Nuclear Proteins RNA-Binding Proteins medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ubiquitin ligase Disease Models Animal Cancer development 030104 developmental biology Oncology Tumor progression 030220 oncology & carcinogenesis Cancer cell Proteolysis biology.protein Cancer research DTL Heterografts CUL4A Carcinogenesis Apoptosis Regulatory Proteins |
Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-13 (2019) Journal of Experimental & Clinical Cancer Research : CR |
ISSN: | 1756-9966 |
Popis: | Background Ubiquitin E3 ligase CUL4A plays important oncogenic roles in the development of cancers. DTL, one of the CUL4-DDB1 associated factors (DCAFs), may involve in the process of cancer development. Programmed cell death 4 (PDCD4) is a tumor suppressor gene involved in cell apoptosis, transformation, invasion and tumor progression. Methods Affinity-purification mass spectrometry was used to identify potential DTL interaction proteins. Co-immunoprecipitation (Co-IP) was performed to verify protein interaction between DTL and PDCD4. mRNA levels in cancer cells and tissues were detected by Quantitative real-time PCR. Lentivirus was used to establish stable overexpression and knocking down cell lines for DTL and PDCD4. Transwell and wound healing assays were used to determine migration ability of cancer cells. Matrigel assay was used to determine invasion ability of cancer cells. MTT and colony formation assays were used to evaluate proliferation of cancer cells. Results In this study, programmed cell death 4 (PDCD4) was identified as a potential substrate of DTL. Co-IP and immunofluorescence assays further confirmed the interaction between DTL and PDCD4. Moreover, DTL overexpression decreased the protein level and accelerated the degradation rate of PDCD4. Through in vitro ubiquitination experiment, we proved that PDCD4 was degraded by DTL through ubiquitination. Clinically DTL was significantly up-regulated in cancer tissues than that in normal tissues. The survival curves showed that cancer patients with higher DTL expression owned lower survival rate. Functional experiments showed that DTL not only enhanced the proliferation and migration abilities of cancer cells, but also promoted the tumorigenesis in nude mice. Rescued experiment results demonstrated that silencing PDCD4 simultaneous with DTL recovered the phenotypes defect caused by DTL knocking down. Conclusions Our results elucidated that DTL enhanced the motility and proliferation of cancer cells through degrading PDCD4 to promote the development of cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1358-x) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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