Research progress on m6A and drug resistance in gastrointestinal tumors

Abstract

Gastrointestinal (GI) tumors represent a significant global health burden and are among the leading causes of cancer-related mortality worldwide. their drug resistance is one of the major challenges in cancer therapy. In recent years, epigenetic modifications, especially N6-methyladenosine (m6A) RNA modifications, have become a hot research topic. m6A modification plays an important role in gene expression and cancer progression by regulating RNA splicing, translation, stability, and degradation, which are regulated by "writers," "erasers" and "readers." In GI tumors, resistance to chemotherapy, targeted therapy, and immunotherapy is closely associated with m6A RNA modification. Therefore, the molecular mechanism of m6A modification and its targeted drug development provide new therapeutic strategies for overcoming drug resistance and therapeutic efficacy in GI tumors. In this review, the biological functions of m6A were explored, the specific resistance mechanisms of m6A in different types of GI tumors were explored, new ideas and targets for future treatment resistance were identified, and the limitations of this field were highlighted.

Keywords: RNA modifications; drug resistance; epigenetic alterations; gastrointestinal tumors; m6A.

FIGURE 1

Overview of key RNA modifications closely linked to cancer progression. The major types of RNA modifications, including 5-methylcytosine (m5C), N1-methyladenosine (m1A), N6-methyladenosine (m6A), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I), focus on the roles of m6A in regulating RNA metabolism. These modifications alter RNA structure and function, impacting key biological processes such as splicing, translation, and stability and degradation. RMs are dynamic and often reversible. RMs are dynamically regulated by “writers,” “readers,” and “erasers.” “Writer” proteins are responsible for transferring methyl groups onto RNA molecules. (e.g., METTL3, METTL14, WTAP and ZC3H13), “readers” recognize and bind to m6A-modified RNA molecules. (e.g., YTHDF proteins, IGF2BPs), and “erasers” remove RNA modifications (e.g., FTO and ALKBH5). The complex interactions among writers, readers, and erasers are critical for cellular adaptations and responses, especially in the context of cancer.

FIGURE 2

The roles of m6A RNA modifications in mediating chemotherapy resistance in gastric and pancreatic cancers. (A) In gastric cancer (GC), dysregulated RNA methylation modulates various pathways to induce resistance to cisplatin (DDP), 5-fluorouracil (5-FU), and oxaliplatin (OXA). The key mechanisms include METTL3-mediated m6A modification, which enhances ARF6 and PARP1 mRNA stability, and hnRNPA2B1, which stabilizes the NEAT1 lncRNA, increasing 5-FU resistance. (B) In pancreatic cancer (PC), m6A modification drives gemcitabine (GEM) resistance. METTL3-mediated m6A methylation stabilizes DDX23 mRNA. FTO stabilizes KDM5B expression and activates DLG1/YAP1 signaling, whereas LINC01134, which is regulated by FTO and YTHDF2, sponges miR-140-3p to activate WNT5A and promote resistance. These findings highlight the complex interplay between RNA modification enzymes and downstream pathways, providing potential therapeutic targets to overcome chemotherapy resistance in digestive system cancers.

FIGURE 3

Roles of m6A RNA modifications in mediating chemotherapy resistance in hepatocellular carcinoma (HCC), colorectal cancer (CRC), and esophageal cancer (ESCA). (A) In HCC, METTL3 modulates sorafenib resistance by stabilizing circRNA-SORE and reducing FOXO3 mRNA stability. (B) In CRC, METTL3 and FTO regulate Sec62 and SIVA1 mRNA, promoting resistance to 5-FU and oxaliplatin. (C) In ESCA, ALKBH5-mediated CASC8 upregulation stabilizes hnRNPL, activating the Bcl2/caspase3 pathway, whereas METTL14 loss promotes radioresistance via TRIB2. These findings underscore m6A regulators as potential therapeutic targets to overcome resistance in gastrointestinal cancers.