Abstract Background RNA methylation, an important reversible post-transcriptional modification in eukaryotes, has emerged as a prevalent epigenetic alteration. However, the role of the m6A reader YTH domain family 2 (YTHDF2) has not been reported in anaplastic thyroid cancer (ATC) and its biological mechanism is unclear. Methods The relationship between YTHDF2 expression and ATC was determined using data sets and tissue samples. A range of analytical techniques were employed to investigate the regulatory mechanism of YTHDF2 in ATC, including bioinformatics analysis, m6A dot-blot analysis, methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, RNA sequencing, RNA stability assays and dual luciferase reporter gene assays. In vitro and in vivo assays were also conducted to determine the contribution of YTHDF2 to ATC development. Results YTHDF2 expression was significantly increased in ATC. The comprehensive in vitro and in vivo experiments demonstrated that YTHDF2 knockdown significantly attenuated ATC proliferation, invasion, migration, and apoptosis promotion, whereas YTHDF2 overexpression yielded the opposite trend. Mechanistically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrated that YTHDF2 accelerated the degradation of DNA damage-inducible transcript 4 or regulated in DNA damage and development 1 (DDIT4, or REDD1) mRNA in an m6A-dependent manner, which in turn activated the AKT/mTOR signaling pathway and induced activation of epithelial-mesenchymal transition (EMT), thereby promoting ATC tumor progression. Conclusions This study is the first to demonstrate that elevated YTHDF2 expression levels suppress DDIT4 expression in an m6A-dependent manner and activate the AKT/mTOR signaling pathway, thereby promoting ATC progression. YTHDF2 plays a pivotal role in ATC progression, and it may serve as a promising therapeutic target in the future.

Bao Dai

Lei Xu

Shikuo Rong

Muye Song

Ziteng Lan

Weijian Chen

Lingyun Zhang

Yongchen Liu

Linhe Wang

Jinghua Li

Jian Chen

Zeyu Wu

Biology Direct

BIOLOGY DIRECT 作为开放获取、同行评审的在线期刊服务于生命科学研究社区，为作者和读者提供了传统同行评审模式的替代方案。 BIOLOGY DIRECT 考虑目前被认为最有利于开放审查方法的学科领域的原创研究文章、假设、评论、发现笔记和评论，主要是那些具有重要非实验成分的领域。

Biology Direct is an open-access, peer-reviewed online journal that serves the life sciences research community. It provides authors and readers with an alternative to the traditional peer review model. Biology Direct considers original research articles, hypotheses, reviews, discovery notes, and commentaries, particularly in fields that are currently viewed as most conducive to open review methods.

《Biology Direct》是一份开放获取、同行评审的在线期刊，旨在服务于生命科学研究社区。它为作者和读者提供了一种传统同行评审模式的替代方案。《Biology Direct》接受原创研究文章、假设、评论、发现笔记和评论，特别关注那些具有重要非实验成分的学科领域。

YTHDF2 promotes anaplastic thyroid cancer progression by activating the DDIT4/AKT/mTOR signaling pathway

This study is the first to demonstrate that elevated YTHDF2 expression levels suppress DDIT4 expression in an m6A-dependent manner and activate the AKT/mTOR signaling pathway and activate the AKT/mTOR signaling pathway, thereby promoting ATC progression.

Category	Quartile
生物学	2
生物学, 生物学	2

YTHDF2 promotes anaplastic thyroid cancer progression by activating the DDIT4/AKT/mTOR signaling pathway

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