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DARS-AS1 recruits METTL3/METTL14 to bind and enhance DARS mRNA m⁶A modification and translation for cytoprotective autophagy in cervical cancer.

ABSTRACT: Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5' untranslated region (5'UTR) and promoting its translation. The present study demonstrated that the 'HIF1α/DARS-AS1/DARS/ATG5/ATG3' pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.

SUBMITTER: Shen W

PROVIDER: S-EPMC9176263 | biostudies-literature |

REPOSITORIES: biostudies-literature

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