Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer
Abstract Background Long noncoding RNAs (lncRNAs) have driven research focused on their effects as oncogenes or tumor suppressors involved in carcinogenesis. However, the functions and mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. Methods The expression of DLGAP1-AS2 was asse...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-022-01675-w |
| _version_ | 1811189440081559552 |
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| author | Xue Wang Han Cheng Jing Zhao Jiuming Li Ying Chen Kaisa Cui Lu Tian Jia Zhang Chaoqun Li Shengbai Sun Yuyang Feng Surui Yao Zehua Bian Shenglin Huang Bojian Fei Zhaohui Huang |
| author_facet | Xue Wang Han Cheng Jing Zhao Jiuming Li Ying Chen Kaisa Cui Lu Tian Jia Zhang Chaoqun Li Shengbai Sun Yuyang Feng Surui Yao Zehua Bian Shenglin Huang Bojian Fei Zhaohui Huang |
| author_sort | Xue Wang |
| collection | DOAJ |
| description | Abstract Background Long noncoding RNAs (lncRNAs) have driven research focused on their effects as oncogenes or tumor suppressors involved in carcinogenesis. However, the functions and mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. Methods The expression of DLGAP1-AS2 was assessed by quantitative RT-PCR in multiple CRC cohorts. The impacts of DLGAP1-AS2 on CRC growth and metastasis were evaluated by a series of in vitro and in vivo assays. Furthermore, the underlying mechanism of DLGAP1-AS2 in CRC was revealed by RNA pull down, RNA immunoprecipitation, RNA sequencing, luciferase assays, chromatin immunoprecipitation, and rescue experiments. Results We discovered that DLGAP1-AS2 promoted CRC tumorigenesis and metastasis by physically interacting with Elongin A (ELOA) and inhibiting its protein stability by promoting tripartite motif containing 21 (Trim21)-mediated ubiquitination modification and degradation of ELOA. In particular, we revealed that DLGAP1-AS2 decreases phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) expression by inhibiting ELOA-mediated transcriptional activating of LHPP and thus blocking LHPP-dependent suppression of the AKT signaling pathway. In addition, we also demonstrated that DLGAP1-AS2 was bound and stabilized by cleavage and polyadenylation specificity factor (CPSF2) and cleavage stimulation factor (CSTF3). Conclusions The discovery of DLGAP1-AS2, a promising prognostic biomarker, reveals a new dimension into the molecular pathogenesis of CRC and provides a prospective treatment target for this disease. |
| first_indexed | 2024-04-11T14:34:52Z |
| format | Article |
| id | doaj.art-174656de1fd443b39c7f46fa6d70bfb7 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-11T14:34:52Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj.art-174656de1fd443b39c7f46fa6d70bfb72022-12-22T04:18:21ZengBMCMolecular Cancer1476-45982022-11-0121111910.1186/s12943-022-01675-wLong noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancerXue Wang0Han Cheng1Jing Zhao2Jiuming Li3Ying Chen4Kaisa Cui5Lu Tian6Jia Zhang7Chaoqun Li8Shengbai Sun9Yuyang Feng10Surui Yao11Zehua Bian12Shenglin Huang13Bojian Fei14Zhaohui Huang15Wuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityLaboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityLaboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityInstitutes of Biomedical Sciences, Fudan University Shanghai Cancer Center, Fudan UniversityDepartment of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan UniversityWuxi Cancer Institute, Affiliated Hospital of Jiangnan UniversityAbstract Background Long noncoding RNAs (lncRNAs) have driven research focused on their effects as oncogenes or tumor suppressors involved in carcinogenesis. However, the functions and mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. Methods The expression of DLGAP1-AS2 was assessed by quantitative RT-PCR in multiple CRC cohorts. The impacts of DLGAP1-AS2 on CRC growth and metastasis were evaluated by a series of in vitro and in vivo assays. Furthermore, the underlying mechanism of DLGAP1-AS2 in CRC was revealed by RNA pull down, RNA immunoprecipitation, RNA sequencing, luciferase assays, chromatin immunoprecipitation, and rescue experiments. Results We discovered that DLGAP1-AS2 promoted CRC tumorigenesis and metastasis by physically interacting with Elongin A (ELOA) and inhibiting its protein stability by promoting tripartite motif containing 21 (Trim21)-mediated ubiquitination modification and degradation of ELOA. In particular, we revealed that DLGAP1-AS2 decreases phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) expression by inhibiting ELOA-mediated transcriptional activating of LHPP and thus blocking LHPP-dependent suppression of the AKT signaling pathway. In addition, we also demonstrated that DLGAP1-AS2 was bound and stabilized by cleavage and polyadenylation specificity factor (CPSF2) and cleavage stimulation factor (CSTF3). Conclusions The discovery of DLGAP1-AS2, a promising prognostic biomarker, reveals a new dimension into the molecular pathogenesis of CRC and provides a prospective treatment target for this disease.https://doi.org/10.1186/s12943-022-01675-wColorectal cancerLong noncoding RNAsDLGAP1-AS2ELOATrim21LHPP |
| spellingShingle | Xue Wang Han Cheng Jing Zhao Jiuming Li Ying Chen Kaisa Cui Lu Tian Jia Zhang Chaoqun Li Shengbai Sun Yuyang Feng Surui Yao Zehua Bian Shenglin Huang Bojian Fei Zhaohui Huang Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer Molecular Cancer Colorectal cancer Long noncoding RNAs DLGAP1-AS2 ELOA Trim21 LHPP |
| title | Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer |
| title_full | Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer |
| title_fullStr | Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer |
| title_full_unstemmed | Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer |
| title_short | Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer |
| title_sort | long noncoding rna dlgap1 as2 promotes tumorigenesis and metastasis by regulating the trim21 eloa lhpp axis in colorectal cancer |
| topic | Colorectal cancer Long noncoding RNAs DLGAP1-AS2 ELOA Trim21 LHPP |
| url | https://doi.org/10.1186/s12943-022-01675-w |
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