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

Objective N6-methyladenosine (m6A) RNA methylation involve in governing mechanism of tumor progression. We aimed to excavate the biological role and mechanism of m6A methyltransferase METTL3 in Cholangiocarcinoma (CCA). Methods METTL3 expression was determined by database and tissue microarray. The role of METTL3 in CCA was explored by loss- and gain-of-function experiments. 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 a poor prognosis in CCA patients. Overexpression of METTL3 facilitated proliferation, migration, invasion, glucose uptake, and lactate production of CCA cells, whereas knockdown of METTL3 had the opposite effect. We further found that METTL3 deficiency inhibited tumor growth of CCA in vivo. RNA sequencing and MeRIP-qPCR confirmed that METTL3 enhanced AKR1B10 expression and m6A modification level. Further, METTL3 directly bind with AKR1B10 at an m6A modification site also confirmed. CCA tissue microarray showed that AKR1B10 expression was upregulated in CCA tissue and silencing of 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 to apply in CCA therapy.