M6A RNA methylation in biliary tract cancer: the function roles and potential therapeutic implications

Abstract

Biliary tract cancers (BTCs) are relatively rare malignancies with a poor prognosis. For advanced BTCs, the efficacy of current chemotherapeutic approaches is limited. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms underlying BTC tumorigenesis and development for the exploration of effective targeted therapies. N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryotes, is found usually dysregulated and involved in tumorigenesis, progression, and drug resistance in tumors. Numerous studies have confirmed that aberrant m6A regulators function as either oncogenes or tumor suppressors in BTCs by the reversible regulation of RNA metabolism, including splicing, export, degradation and translation. In this review, we summarized the current roles of the m6A regulators and their functional impacts on RNA fate in BTCs. The improved understanding of m6A modification in BTCs also provides a reasonable outlook for the exploration of new diagnostic strategies and efficient therapeutic targets.

Fig. 1. The molecular mechanism of m6A RNA modification.

“Writers” catalyze the deposition of methylation. “Erasers” remove the m6A modification from RNA. “Readers” recognize m6A-binding sites and mediate RNA processing, splicing, exportion, translation, stabilization and decay.

Fig. 2. Function of m6A in BTCs.

m6A regulators act as oncogenes or tumor suppressors through m6A depended regulation of the target RNAs in BTCs.

Fig. 3. The anti-tumor effects of FTO inhibitor.

FTO inhibitor acts anti-tumor activity in an m6A-depended manner, especially in cases with IDH1/2 mutation. R-2HG promotes tumorigenesis while also increasing abundance of m6A modifications through inhibiting FTO, and exhibiting anti-tumor effects.