DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation

Abstract

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.

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“…CENPE functioned as an oncogene and promoted the progression of various types of cancers including lung cancer, esophageal adenocarcinoma, and prostate cancer. [17][18][19] DTL was found to promote cancer progression by PDCD4 ubiquitin-dependent degradation 20 and DTL depletion inhibited liver cancer cell growth, increased senescence, and reduced tumorigenesis. 21 FANCI was functioned as a DNA-repair protein and has been found to be involved in the breast cancer progression.…”

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“…Reportedly, DTL overexpression decreased the protein level and accelerated the degradation rate of PDCD4 by ubiquitination and in cancer tissues was significantly upregulated than in normal tissues [32]. Moreover, cancer patients with higher DTL expression owned lower survival rate, and functional experiments found that DTL enhanced the motility and proliferation of cancer cells through degrading PDCD4 to promote the development of cancers [32]. A recent study showed that DTL, as one of the nine hub genes, played a role in type 2 diabetes mellitus and hepatocellular carcinoma (HCC) [33].…”

“…PEST domain of AHCYL2 interacts with the NBCe1-B, which plays a critical role in neuronal modulation and intracellular pH regulation during activity [30,31]. Reportedly, DTL overexpression decreased the protein level and accelerated the degradation rate of PDCD4 by ubiquitination and in cancer tissues was significantly upregulated than in normal tissues [32]. Moreover, cancer patients with higher DTL expression owned lower survival rate, and functional experiments found that DTL enhanced the motility and proliferation of cancer cells through degrading PDCD4 to promote the development of cancers [32].…”