Dataset Information

Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma.

ABSTRACT: N6-methyladenosine (m⁶A) RNA modification is the most common internal mRNA modification in mammals and has been reported to play a key role in gene expression regulation. In this study, we detected a high level of m⁶A methylation of the PLOD2 3'-untranslated regions (3'UTR) in renal cell carcinoma (RCC). Furthermore, we found that the high expression level of PLOD2 was a prognostic indicator for patients with RCC. A dm⁶ACRISPR demethylation system was performed to accurately and specifically demethylate 3'UTR of PLOD2 and caused an inactivation of PLOD2 expression. Furthermore, we also performed many in vitro experiments to confirm that PLOD2 exerted tumor promoter effects by promoting tumor proliferation and migration. In conclusion, PLOD2 mRNA demethylated by dCas13b-ALKBH5 might provide a new light on the treatment for RCC.

SUBMITTER: Cao C

PROVIDER: S-EPMC8220145 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma.

Cao Congcong C Ma Qian Q Huang Xinbo X Li Aolin A Liu Jun J Ye Jing J Gui Yaoting Y

Frontiers in molecular biosciences 20210609

N6-methyladenosine (m6A) RNA modification is the most common internal mRNA modification in mammals and has been reported to play a key role in gene expression regulation. In this study, we detected a high level of m6A methylation of the PLOD2 3'-untranslated regions (3'UTR) in renal cell carcinoma (RCC). Furthermore, we found that the high expression level of PLOD2 was a prognostic indicator for patients with RCC. A dm6ACRISPR demethylation system was performed t ...[more]

PMID: 34179084

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Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1's carcinogenic effects in ccRCC.MethodsExpression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways.ResultsThe expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05).ConclusionsThis study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC.

Dataset Information

Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma.

Publications

Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma.

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