Dataset Information

METTL3 Induces AAA Development and Progression by Modulating N6-Methyladenosine-Dependent Primary miR34a Processing.

ABSTRACT: Identifying effective drugs to delay the progression of aortic aneurysms is a formidable challenge in vascular medicine. Methyltransferase-like 3 (METTL3) plays a key role in catalyzing the formation of N6-methyladenosine (m6A), but despite the functional importance of METTL3 and m6A in various fundamental biological processes, their roles in abdominal aortic aneurysm (AAA) are unknown. Here, we found that METTL3 knockdown in apolipoprotein E-deficient (ApoE-/-) mice treated with angiotensin II suppressed the formation of AAAs, while METTL3 overexpression exerted the opposite effects. Similar results were obtained in a calcium chloride (CaCl2)-induced mouse AAA model. Mechanistically, METTL3-dependent m6A methylation promoted primary microRNA-34a (miR-34a, pri-miR34a) maturation through DGCR8. Moreover, miR-34a overexpression significantly decreased SIRT1 expression and aggravated AAA formation, while miR-34a deficiency produced the opposite effects. In a rescue experiment, miR-34a knockdown or forced expression of SIRT1 partially attenuated the protective effects of METTL3 deficiency against AAA formation. Our studies reveal an important role for METTL3/m6A-mediated miR-34a maturation in AAA formation and provide a novel therapeutic target and diagnostic biomarker for AAA treatment.

SUBMITTER: Zhong L

PROVIDER: S-EPMC7347714 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

METTL3 Induces AAA Development and Progression by Modulating N6-Methyladenosine-Dependent Primary miR34a Processing.

Zhong Lintao L He Xiang X Song Haoyu H Sun Yili Y Chen Guojun G Si Xiaoyun X Sun Jie J Chen Xiaoqiang X Liao Wangjun W Liao Yulin Y Bin Jianping J

Molecular therapy. Nucleic acids 20200610

Identifying effective drugs to delay the progression of aortic aneurysms is a formidable challenge in vascular medicine. Methyltransferase-like 3 (METTL3) plays a key role in catalyzing the formation of N6-methyladenosine (m6A), but despite the functional importance of METTL3 and m6A in various fundamental biological processes, their roles in abdominal aortic aneurysm (AAA) are unknown. Here, we found that METTL3 knockdown in apolipoprotein E-deficient (ApoE-/-) ...[more]

PMID: 32650237

Similar Datasets

Project description:BackgroundChemotherapy is an important strategy for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+HER2-) breast cancer (BC), but this subtype has a low response rate to chemotherapy. Growing evidence indicates that N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still important.MethodsmRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction and western blotting, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. Cell cycle progression was assessed by flow cytometry. Cell migration and invasion were analysed by wound healing assays and transwell assays, respectively, and apoptosis was analysed by TUNEL assays. Finally, m6A modification was analysed by methylated RNA immunoprecipitation.ResultsChemotherapy-induced downregulation of the m6A modification is regulated by METTL3 depletion in HR+HER2- BC. METTL3 knockdown in MCF-7/T47D cells decreased the drug sensitivity of HR+HER2- BC cells by promoting tumour proliferation and migration and inhibiting apoptosis. Mechanistically, CDKN1A is a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, a decrease in BAX expression was observed when m6A modification was inhibited with METTL3 knockdown, and apoptosis was inhibited by the reduction of caspase-3/-9/-8.ConclusionMETTL3 depletion promotes the proliferation and migration and decreases the drug sensitivity of HR+HER2- BC via regulation of the CDKN1A/EMT and m6A-BAX/caspase-9/-3/-8 signalling pathways, which suggests METTL3 played a tumour-suppressor role and it could be a potential biomarker for predicting the prognosis of patients with HR+HER2- BC.

Dataset Information

METTL3 Induces AAA Development and Progression by Modulating N6-Methyladenosine-Dependent Primary miR34a Processing.

Publications

METTL3 Induces AAA Development and Progression by Modulating N6-Methyladenosine-Dependent Primary miR34a Processing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets