Writers, readers, and erasers RNA modifications and drug resistance in cancer

Abstract

Drug resistance in cancer cells significantly diminishes treatment efficacy, leading to recurrence and metastasis. A critical factor contributing to this resistance is the epigenetic alteration of gene expression via RNA modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing. These modifications are pivotal in regulating RNA splicing, translation, transport, degradation, and stability. Governed by "writers," "readers," and "erasers," RNA modifications impact numerous biological processes and cancer progression, including cell proliferation, stemness, autophagy, invasion, and apoptosis. Aberrant RNA modifications can lead to drug resistance and adverse outcomes in various cancers. Thus, targeting RNA modification regulators offers a promising strategy for overcoming drug resistance and enhancing treatment efficacy. This review consolidates recent research on the role of prevalent RNA modifications in cancer drug resistance, with a focus on m6A, m1A, m5C, m7G, Ψ, and A-to-I editing. Additionally, it examines the regulatory mechanisms of RNA modifications linked to drug resistance in cancer and underscores the existing limitations in this field.

Keywords: Abnormal expression; Combination therapy; Drug resistance; Epigenetic alterations; RNA modification regulators.

Fig. 1

Overview of main RNA modifications closely associated with cancer development. The most critical RNA modifications implicated in tumorigenesis include 7-methylguanosine (m7G), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N6-methyladenosine (m6A), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing. These modifications alter the chemical structure of RNAs, directly affecting gene expression and various biological processes. RNA modifications are dynamic and often reversible. “Writer” proteins add chemical groups to RNA molecules, thereby enhancing or modifying their function. “Readers” identify and bind to these modified RNAs, influencing subsequent RNA processing steps such as splicing, localization, export, translation, stability, and degradation. Conversely, “erasers” remove RNA modifications, potentially restoring the original RNA functions. The intricate interplay among writers, readers, and erasers is essential for cellular responses and adaptations, particularly in cancer cells

Fig. 2

Mechanisms of abnormal RNA modifications. Aberrant RNA modifications can drive cancer progression through complex genetic and environmental interactions within the tumor microenvironment. These modifications often result from genetic mutations in enzymes that add or remove methyl groups, or in RNA-binding proteins, as well as from mutations in target genes that disrupt normal RNA modification processes

Fig. 3

General Mechanisms of abnormal RNA modifications in drug resistance. Aberrant RNA modifications and their regulators are frequently linked to chemotherapy resistance in various cancers, including those of the digestive, genitourinary, and respiratory systems, as well as hematologic malignancies. These modifications can alter gene expression, affect DNA damage repair (DDR), and induce immune evasion, thereby contributing to drug resistance. Collectively, these drug resistance-related processes accelerate cancer progression, underscoring the significant role of RNA modifications in shaping the malignant behavior of cancer cells and influencing therapeutic outcomes

Fig. 4

Mechanisms of abnormal RNA modifications involved in chemotherapy resistance in digestive system cancers. Abnormal RNA methylation significantly contributes to chemotherapy resistance in digestive system cancers. In pancreatic cancer, METTL3-mediated m6A methylation of lncRNA FOXD1-AS1 enhances 5-FU resistance by promoting cell self-renewal through miR-570-3p sequestration. In gastric cancer, HNRNPA2B1 stabilizes lncRNA NEAT1, activating the Wnt/β-catenin pathway and increasing 5-FU resistance. Additionally, the dysregulation of RNA modification enzymes such as ALKBH5 affects gemcitabine sensitivity in pancreatic cancer by altering WIF-1 mRNA methylation and influencing the Wnt signaling pathway. These examples highlight the complex role of RNA methylation in modulating drug response and resistance across various gastrointestinal cancers

Fig. 5

Mechanisms of abnormal RNA modifications involved in chemotherapy resistance in genitourinary system cancers Aberrant RNA modifications are frequently linked to chemotherapy resistance by altering gene expression and signaling pathways in genitourinary system cancers, including breast, ovarian, cervical, prostate, and bladder cancers. In breast cancer, METTL3 enhances ADR resistance by methylating EGF mRNA, which increases homologous recombination (HR) repair efficiency and reduces DNA damage. In ovarian cancer, elevated ALKBH5 levels increase cisplatin resistance by demethylating HOXA10, thereby promoting cell proliferation. Cervical cancer shows increased CENPK expression via ZC3H13-mediated mRNA methylation, which enhances stemness and drug resistance. Conversely, in bladder cancer, downregulation of ALKBH5 is associated with improved cisplatin sensitivity due to reduced CK2α-mediated glycolysis. Targeting RNA methylation pathways thus presents a promising strategy for overcoming drug resistance in genitourinary system cancers

Fig. 6

Mechanisms of abnormal RNA modifications involved in chemotherapy resistance in hematologic malignancies and respiratory system cancers. Abnormal RNA methylation plays a significant role in chemotherapy resistance across various cancers. In leukemia, IGF2BP1 enhances resistance by regulating genes such as HOXB4 and MYB, impacting responses to treatments like ATRA and doxorubicin. METTL3 further contributes to resistance through m6A methylation of ITGA4, affecting homing and engraftment. Additionally, LINC00470 decreases PTEN expression via METTL3, activating AKT signaling and increasing resistance to ADR. In multiple myeloma, elevated METTL7A levels promote chemotherapy evasion by enhancing exosomal mechanisms. In lung cancer and nasopharyngeal carcinoma, higher levels of METTL3 and METTL5 lead to chemoresistance by activating mitochondrial autophagy and enhancing the translation of oncogenic factors, respectively. These findings underscore the complex role of RNA modifications in treatment resistance, highlighting the urgent need for targeted therapeutic strategies

Fig. 7

Mechanisms of abnormal RNA modifications involved in resistance to targeted therapy and immunotherapy in cancer. Beyond contributing to chemotherapy resistance, abnormal RNA modifications can diminish the efficacy of targeted therapies and immunotherapies, resulting in treatment failure or cancer recurrence. Modifications such as m6A, m7G, m5C, and A-to-I editing promote resistance to tyrosine kinase inhibitors in various cancers, including hepatocellular carcinoma, leukemia, and lung cancer. For example, METTL3 reduces the therapeutic efficacy of the BRAF inhibitor PLX4032 in melanoma by activating the epidermal growth factor receptor (EGFR) pathway. Additionally, RNA modifications can disrupt gene expression and intracellular signaling pathways, leading to abnormal expression of immune checkpoints, interference with antigen presentation and recognition, suppression of cytotoxic T-cell infiltration, and the development of immunotherapy resistance