METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10

Abstract

Objective N6-methyladenosine (m6A) RNA methylation is involved in governing the mechanism of tumor progression. We aimed to excavate the biological role and mechanism of the m6A methyltransferase METTL3 in cholangiocarcinoma (CCA). Methods METTL3 expression was determined by database and tissue microarray analyses. The role of METTL3 in CCA was explored by loss- and gain-of-function experiments. The m6A target of METTL3 was detected by RNA sequencing. The role of AKR1B10 in CCA was explored, and the association between METTL3 and AKR1B10 was confirmed by rescue experiments. Result METTL3 expression was upregulated in CCA tissue, and higher METTL3 expression was implicated in poor prognoses in CCA patients. Overexpression of METTL3 facilitated proliferation, migration, invasion, glucose uptake, and lactate production in CCA cells, whereas knockdown of METTL3 had the opposite effects. We further found that METTL3 deficiency inhibited CCA tumor growth in vivo. RNA sequencing and MeRIP-qPCR confirmed that METTL3 enhanced AKR1B10 expression and m6A modification levels. Furthermore, METTL3 directly binds with AKR1B10 at an m6A modification site. A CCA tissue microarray showed that AKR1B10 expression was upregulated in CCA tissue and that silencing AKR1B10 suppressed the malignant phenotype mentioned above in CCA. Notably, knockdown of AKR1B10 rescued the tumor-promoting effects induced by METTL3 overexpression. Conclusion Elevated METTL3 expression promotes tumor growth and glycolysis in CCA through m6A modification of AKR1B10, indicating that METTL3 is a potential target for blocking glycolysis for application in CCA therapy.

METTL3 as a novel diagnosis and treatment biomarker and its association with glycolysis, cuproptosis and ceRNA in oesophageal carcinoma

“…METTL3, an important RNA methyltransferase, plays a critical role in RNA modification, and its expression and catalysed RNA m6A modification are associated with the occurrence and progression of various human diseases 10–12,14 . Prior studies have demonstrated that METTL3 is overexpressed in various cancers and contributes to cancer progression and metastasis 21,46–55 . In this study, we further confirmed through multi‐data set analysis that the expression of METTL3 was significantly higher in tumour samples than in the control group.…”

“…[10][11][12]14 Prior studies have demonstrated that METTL3 is overexpressed in various cancers and contributes to cancer progression and metastasis. 21,[46][47][48][49][50][51][52][53][54][55] In this study, we further confirmed through multi-data set analysis that the expression of METTL3 was significantly higher in tumour samples than in the control group. ROC results indicated that its expression the expression of ER target genes and limits the growth of breast cancer cells.…”

Prognostic significance of 18F-Fluorodeoxyglucose positron-emission tomography parameters in patients with biliary tract cancers: a meta-analysis

“…previous studies demonstrated that glycolysis, as metabolic reprogramming, contributed significantly to cholangiocarcinoma initiation and progression [ 43 , 44 ] Glycolic pathways and enzymes, including pyruvate kinase M2 [ 45 , 46 ], Aldolase A [ 47 ] and lactate dehydrogenase A [ 48 ], play a critical role in BTC and have been utilized as biomarkers to predict patients` outcomes. Targeting glycolysis could be considered as a promising treatment option in BTC [ 49 – 51 ].…”

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

“…In mechanism, YTHDF2 accelerated degradation of m6A-modified LATS1 mRNA, thus reduced phosphorylation of YAP/TAZ and activated it. 223 In addition to these compelling transcription factors (TFs), METTL3 boosted expression of NDUFA4 in GC, 224 AKR1B10 in cholangiocarcinoma (CCA), 225 NCAPH in clear cell renal cell carcinomas (ccRCC), 226 thus promoted glycolysis and malignant phenotypes. Notably, METTL3-induced m6A interacted with ncRNAs to improve glycolysis, such as stabilizing effects on lncRNA ABHD11-AS1 in NSCLC, 227 lncRNA SNHG7 in prostate cancer (PC), 228 circQSOX1 in CRC, 229 and linc-UROD in PC, 230 which are generally mediated by IGF2BPs.…”