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C-Jun-mediated ?-1,3-N-acetylglucosaminyltransferase 8 expression: A novel mechanism regulating the invasion and metastasis of colorectal carcinoma cells.

ABSTRACT: ?-1,3-N-Acetylglucosaminyltransferase 8 (?3GnT8) is a key enzyme that catalyzes the formation of polylactosamine glycan structures by transferring GlcNAc to tetra-antennary ?1-6-branched N-glycans, and it has been reported to participate in tumor invasion and metastasis by regulating the expression of matrix metalloproteinases (MMPs), cluster of differentiation 147 (CD147) and polylactosamine. By contrast, the role of transcription factor c-Jun in cell cycle progression has been well established. c-Jun has an important role in tumor cell invasion and metastasis. However, the precise molecular mechanisms by which c-Jun regulates these processes in colorectal carcinoma cells are not fully elucidated. In the present study, c-Jun had a significant effect on the invasive and migratory abilities of SW480 and LoVo cells. Additionally, overexpression of c-Jun was able to increase the expression of ?3GnT8, MMPs, CD147 and polylactosamine. Similarly, knockdown of c-Jun was able to decrease the expression of ?3GnT8, MMPs, CD147 and polylactosamine. These results suggest that c-Jun is able to regulate colorectal carcinoma cell invasion and metastasis via ?3GnT8. A chromatin immunoprecipitation assay indicated that c-Jun is able to bind directly to the promoter regions of ?3GnT8 in SW480 and LoVo cells. This leads to transcriptional activation of ?3GnT8, which in turn regulates the expression of tumor invasion and metastasis-associated genes. The results of the present study demonstrate a novel mechanism underlying colorectal carcinoma cell invasion and metastasis, where ?3GnT8 is transcriptionally activated via c-Jun binding to its promoter.

SUBMITTER: Liu C

PROVIDER: S-EPMC5587945 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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c-Jun-mediated β-1,3-N-acetylglucosaminyltransferase 8 expression: A novel mechanism regulating the invasion and metastasis of colorectal carcinoma cells.

Liu Chunliang C Qiu Hao H Yu Meiyun M Wang Zerong Z Yuan Yaqin Y Jiang Zhi Z Shao Xuejun X Hua Dong D Liu Min M Wu Shiliang S

Oncology letters 20170720 3

β-1,3-N-Acetylglucosaminyltransferase 8 (β3GnT8) is a key enzyme that catalyzes the formation of polylactosamine glycan structures by transferring GlcNAc to tetra-antennary β1-6-branched N-glycans, and it has been reported to participate in tumor invasion and metastasis by regulating the expression of matrix metalloproteinases (MMPs), cluster of differentiation 147 (CD147) and polylactosamine. By contrast, the role of transcription factor c-Jun in cell cycle progression has been well established ...[more]

PMID: 28927138

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Project description:BackgroundMetastasis is the leading cause of death among patients with colorectal cancer (CRC). Therefore, it is important to explore the molecular mechanisms of metastasis to develop effective therapeutic targets for CRC. In the present study, ribosomal protein L21 (RPL21) was considered as being involved in promoting CRC metastasis, yet the underlying mechanism requires further investigation.MethodsImmunohistochemistry, western blotting, and quantitative reverse transcription polymerase chain reaction were performed to measure the expression of RPL21 and lysosome-associated membrane protein 3 (LAMP3) in CRC tissues and cells. Wound healing, transwell migration, and invasion assays were performed to study the migration and invasion of cultured CRC cells. An orthotopic CRC mouse model was developed to investigate the metastatic ability of CRC. Transcriptome sequencing was conducted to identify the genes related to RPL21. The dual-luciferase reporter gene assay was performed to determine the transcriptional activity of transcription factor EB (TFEB). The GST/His pull-down assay was performed to investigate the specific binding sites of RPL21 and LAMP3. The cell adhesion assay was performed to determine the adhesion ability of CRC cells. Immunofluorescence staining was performed to observe focal adhesions (FAs).ResultsRPL21 was highly expressed in CRC, contributing to tumor invasiveness and poor patient prognosis. Functionally, RPL21 promoted the migration and invasion of CRC cells in vitro and tumor metastasis in vivo. Moreover, LAMP3 was identified as being highly related to RPL21 and was essential in promoting the migration and invasion of CRC cells. Mechanistically, RPL21 activated the transcriptional function of TFEB to upregulate LAMP3 expression. RPL21 directly bound to the aa 341-416 domain of LAMP3 via its aa 1-40 and aa 111-160 segments. The combination of RPL21 and LAMP3 enhanced the stability of the RPL21 protein by suppressing the degradation of the ubiquitin-proteasome system. Furthermore, RPL21 and LAMP3 promoted the formation of immature FAs by activating the FAK/paxillin/ERK signaling pathway.ConclusionsRPL21 promoted invasion and metastasis by regulating FA formation in a LAMP3-dependent manner during CRC progression. The interaction between RPL21 and LAMP3 may function as a potential therapeutic target against CRC.

Dataset Information

C-Jun-mediated ?-1,3-N-acetylglucosaminyltransferase 8 expression: A novel mechanism regulating the invasion and metastasis of colorectal carcinoma cells.

Publications

c-Jun-mediated β-1,3-N-acetylglucosaminyltransferase 8 expression: A novel mechanism regulating the invasion and metastasis of colorectal carcinoma cells.

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