N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma
Abstract Background Hepatocellular carcinoma (HCC) ranks fourth among the malignancies leading to cancer‐related deaths all around the world. It is increasingly evident that long non‐coding RNAs (lncRNAs) are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N6‐methyl...
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| Format: | Article |
| Language: | English |
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Wiley
2022-11-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1107 |
| _version_ | 1797781005799522304 |
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| author | Jiandong Liu Nasha Zhang Jiajia Zeng Teng Wang Yue Shen Chi Ma Ming Yang |
| author_facet | Jiandong Liu Nasha Zhang Jiajia Zeng Teng Wang Yue Shen Chi Ma Ming Yang |
| author_sort | Jiandong Liu |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) ranks fourth among the malignancies leading to cancer‐related deaths all around the world. It is increasingly evident that long non‐coding RNAs (lncRNAs) are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N6‐methyladenosine (m6A) regulates gene expression by impacting multiple aspects of mRNA metabolism. However, there are still no reports on genome‐wide screening and functional annotation of m6A‐methylated lncRNAs in HCC. Methods The m6A modification and biologic functions of ARHGAP5‐AS1 in HCC were investigated through a series of biochemical assays. Clinical implications of ARHGAP5‐AS1 were examined in tissues from HCC patients. Results After systematically analysing the m6A‐seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m6A levels. Among these lncRNAs, we found that ARHGAP5‐AS1 is the lncRNA with the highest levels of m6A modification and significantly increased expression in HCC specimens. METTL14 acts as the m6A writer of ARHGAP5‐AS1 and IGF2BP2 stabilises the lncRNA as its m6A reader. ARHGAP5‐AS1 remarkably promotes malignant behaviours of HCC cells ex vivo and in vivo. We identified oncoprotein CSDE1 working as the interacting protein of the lncRNA and TRIM28 as the E3 ligase of CSDE1 in HCC. Interestingly, ARHGAP5‐AS1 could attenuate interactions between CSDE1 and TRIM28, which prevents the degradation of CSDE1 via the ubiquitin‐proteasome pathway. Elevated levels of CSDE1 coordinate oncogenic RNA regulons, promote translation of VIM and RAC1 and activate the ERK pathway, which contributes to HCC prognosis. Conclusions Our study reveals a new paradigm in m6A‐modified lncRNAs controlling CSDE1‐mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC. |
| first_indexed | 2024-03-12T23:51:41Z |
| format | Article |
| id | doaj.art-da280a96d96743118b1a50bc9ff2e5ee |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-03-12T23:51:41Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-da280a96d96743118b1a50bc9ff2e5ee2023-07-13T14:36:42ZengWileyClinical and Translational Medicine2001-13262022-11-011211n/an/a10.1002/ctm2.1107N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinomaJiandong Liu0Nasha Zhang1Jiajia Zeng2Teng Wang3Yue Shen4Chi Ma5Ming Yang6Shandong Provincial Key Laboratory of Radiation Oncology Cancer Research Center Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan Shandong Province ChinaDepartment of Radiation Oncology Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan Shandong Province ChinaShandong Provincial Key Laboratory of Radiation Oncology Cancer Research Center Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan Shandong Province ChinaShandong University Cancer Center Jinan Shandong Province ChinaShandong University Cancer Center Jinan Shandong Province ChinaShandong University Cancer Center Jinan Shandong Province ChinaShandong Provincial Key Laboratory of Radiation Oncology Cancer Research Center Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan Shandong Province ChinaAbstract Background Hepatocellular carcinoma (HCC) ranks fourth among the malignancies leading to cancer‐related deaths all around the world. It is increasingly evident that long non‐coding RNAs (lncRNAs) are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N6‐methyladenosine (m6A) regulates gene expression by impacting multiple aspects of mRNA metabolism. However, there are still no reports on genome‐wide screening and functional annotation of m6A‐methylated lncRNAs in HCC. Methods The m6A modification and biologic functions of ARHGAP5‐AS1 in HCC were investigated through a series of biochemical assays. Clinical implications of ARHGAP5‐AS1 were examined in tissues from HCC patients. Results After systematically analysing the m6A‐seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m6A levels. Among these lncRNAs, we found that ARHGAP5‐AS1 is the lncRNA with the highest levels of m6A modification and significantly increased expression in HCC specimens. METTL14 acts as the m6A writer of ARHGAP5‐AS1 and IGF2BP2 stabilises the lncRNA as its m6A reader. ARHGAP5‐AS1 remarkably promotes malignant behaviours of HCC cells ex vivo and in vivo. We identified oncoprotein CSDE1 working as the interacting protein of the lncRNA and TRIM28 as the E3 ligase of CSDE1 in HCC. Interestingly, ARHGAP5‐AS1 could attenuate interactions between CSDE1 and TRIM28, which prevents the degradation of CSDE1 via the ubiquitin‐proteasome pathway. Elevated levels of CSDE1 coordinate oncogenic RNA regulons, promote translation of VIM and RAC1 and activate the ERK pathway, which contributes to HCC prognosis. Conclusions Our study reveals a new paradigm in m6A‐modified lncRNAs controlling CSDE1‐mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC.https://doi.org/10.1002/ctm2.1107ARHGAP5‐AS1N6‐methyladenosinelncRNACSDE1hepatocellular carcinoma |
| spellingShingle | Jiandong Liu Nasha Zhang Jiajia Zeng Teng Wang Yue Shen Chi Ma Ming Yang N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma Clinical and Translational Medicine ARHGAP5‐AS1 N6‐methyladenosine lncRNA CSDE1 hepatocellular carcinoma |
| title | N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma |
| title_full | N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma |
| title_fullStr | N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma |
| title_full_unstemmed | N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma |
| title_short | N6‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma |
| title_sort | n6 methyladenosine modified lncrna arhgap5 as1 stabilises csde1 and coordinates oncogenic rna regulons in hepatocellular carcinoma |
| topic | ARHGAP5‐AS1 N6‐methyladenosine lncRNA CSDE1 hepatocellular carcinoma |
| url | https://doi.org/10.1002/ctm2.1107 |
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