YTHDF2 Inhibits the Migration and Invasion of Lung Adenocarcinoma by Negatively Regulating the FAM83D-TGFβ1-SMAD2/3 Pathway

Abstract

ObjectiveYTH domain family 2 (YTHDF2) is an important N6-methyladenosine (m6A) reader, but its role in lung adenocarcinoma remains elusive. This study assessed its function in lung adenocarcinoma.MethodsYTHDF2 expression in lung adenocarcinoma was explored using public databases, such as The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumour Analysis Consortium (CPTAC). The effect of YTHDF2 on a lung adenocarcinoma cell line was explored by performing cytological and molecular experiments. Molecules downstream of YTHDF2 were identified using proteomics, and the related pathways were verified through cytological and molecular biology experiments.ResultsYTHDF2 expression was upregulated in lung adenocarcinoma, and patients with high YTHDF2 expression experienced prolonged overall survival. In two lung cancer cell lines, YTHDF2 knockdown inhibited proliferation but promoted migration, invasion, and the epithelial-mesenchymal transition. The proteomic analysis identified 142 molecules downstream of YTHDF2, and 11 were closely related to survival. Further experiments revealed that YTHDF2 inhibited expression of the family with sequence similarity 83D (FAM83D)-TGFβ1-SMAD2/3 pathway components. This study is the first to show that YTHDF2 regulated the downstream TGFβ1-SMAD2/3 pathway through FAM83D in lung adenocarcinoma.ConclusionYTHDF2 inhibits the migration and invasion of lung adenocarcinoma cells by regulating the FAM83D-TGFβ1-pSMAD2/3 pathway, which may play an important role in lung cancer metastasis.

The mRNA m6A reader YTHDF2 suppresses the proliferation and migration of pterygium fibroblasts

“…EGFR is the target of YTHDF2 and inhibits the proliferation and growth of HCC cells by mediating the MEK/ERK pathway 13 . In addition, YTHDF2 is also engaged in the TGFB1-PSMad 2/3 pathway and the AKT pathway, these pathways can induce the proliferation and migration of pterygium broblast 23,24 . Whether these pathways are involved in the proliferation and migration of pterygium deserves further investigation.…”

Potential impact of WTAP and YTHDF2 on tumor immunity in lung adenocarcinoma

“…WTAP is expressed at low levels in LUAD tissues, and it was shown that PCGEM1 can accelerate the progression of NSCLC by inducing miR-433-3p to upregulate WTAP, [ 26 ] This demonstrates that WTAP is a risk factor for lung cancer YTHDF2 inhibits LUAD cell migration and invasion through regulation of the FAM83D-TGFβ1-pSMAD2/3 pathway, suggesting that YTHDF2 is a lung cancer suppressor [ 27 ] Although WTAP and YTHDF2 have been shown to correlate with response to anti-PD1 therapy in hepatocellular carcinoma. [ 28 ] However, the relationship between WTAP and YTHDF2 expression and immunotherapy response in LUAD patients remains to be investigated.…”

Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer

“…According to Chang et al, YTHDF3 promotes breast cancer brain metastasis by inducing the upregulation of ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (ST6GALNAC5), gap junction protein (GJA1), and EGFR, whose transcripts are enriched in m 6 A modifications [96]. The inhibitory effect of YTHDF2 on the metastasis of lung adenocarcinoma was also investigated [97].…”