DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation

Autor: Maoxiao Feng, Guangwei Wei, Haoran Cui, Zhongxi Zhao, Yunshan Wang, Zhenchuan Lei, Qin Wang
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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