期刊
CELL DEATH DISCOVERY
卷 8, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41420-022-00827-7
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类别
资金
- Guangdong Provincial Bio-engineering Research Center for Gastroenterology Diseases
- National Natural Science Funds of China [82072758, 82073066]
- Guangdong Basic and Applied Basic Research Fund [2021A1515010992, 2020A1515110916, 2019A1515110078]
- Guangdong Medical Science and Technology Research Fund Project [A2020143]
- College Students' Innovative Entrepreneurial Training Plan Program [X202012121322, S202012121089, S202012121090]
- China's Postdoctoral Science Fund [2019M663005]
- Foundation of Nanfang Hospital, Southern Medical University [2018C027, 2019B014]
- Guangzhou Science and technology plan project
- National Program on Key Research Project [2016YFC0901402]
DDX39B has been found to play a pivotal role in the proliferation of human colorectal cancer cells by promoting the cell cycle transition and upregulating the expression of CDK6/CCND1, suggesting it could be a potential therapeutic target.
DDX39B (also called UAP56 or BAT1) which is a kind of DEAD-box family helicase plays pivotal roles in mRNA binding, splicing, and export. It has been found upregulated in many kinds of tumors as an oncogene. Nevertheless, the underlying molecular mechanisms of DDX39B in the proliferation of human colorectal cancer (CRC) remain fairly elusive. In our study, function experiments including the CCK8 and colony formation assay revealed that DDX39B facilitates CRC proliferation in vitro. DDX39B knockdown cells were administered for the orthotopic CRC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry (IHC) was performed to prove that DDX39B can also facilitates CRC proliferation in vivo. Flow cytometry demonstrated that DDX39B promotes the proliferation of CRC cells by driving the cell cycle from G0/G1 phase to the S phase. Mechanistically, RNA-binding protein immunoprecipitation-sequencing (RIP-seq) confirmed that DDX39B binds directly to the first exon of the CDK6/CCND1 pre-mRNA and upregulates their expression. Splicing experiments in vitro using a RT-PCR and gel electrophoresis assay confirmed that DDX39B promotes CDK6/CCND1 pre-mRNA splicing. Rescue experiments indicated that CDK6/CCND1 is a downstream effector of DDX39B-mediated CRC cell proliferation. Collectively, our results demonstrated that DDX39B and CDK6/CCND1 direct interactions serve as a CRC proliferation promoter, which can accelerate the G1/S phase transition to enhance CRC proliferation, and can offer novel and emerging treatment strategies targeting this cell proliferation-promoting gene.
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