The Impact of m6A RNA Modification in Therapy Resistance of Cancer: Implication in Chemotherapy, Radiotherapy, and Immunotherapy

Abstract

m6A RNA methylation, which serves as a critical regulator of transcript expression, has gathered tremendous scientific interest in recent years. From RNA processing to nuclear export, RNA translation to decay, m6A modification has been studied to affect various aspects of RNA metabolism, and it is now considered as one of the most abundant epitranscriptomic modification. RNA methyltransferases (writer), m6A-binding proteins (readers), and demethylases (erasers) proteins are frequently upregulated in several neoplasms, thereby regulating oncoprotein expression, augmenting tumor initiation, enhancing cancer cell proliferation, progression, and metastasis. Though the potential role of m6A methylation in growth and proliferation of cancer cells has been well documented, its potential role in development of therapy resistance in cancer is not clear. In this review, we focus on m6A-associated regulation, mechanisms, and functions in acquired chemoresistance, radioresistance, and resistance to immunotherapy in cancer.

Keywords: ALKBH5; METTL3; PD-1; YTHDF1; cisplatin; m6A methylation.

Figure 1

Overview of m6A regulation in Chemotherapy, Immunotherapy, and Radiotherapy- 1) Chemotherapeutic drugs Cisplatin, Kinase inhibitor modulates m6A regulator (Writer-METTL3, Raeder-YTHDF1, Eraser-ALKBH5, FTO) stabilizes the oncogene mRNA and induces chemoresistance. 2) Tumor immuno microenvironment (TIME) (B cells, dendritic cells, T cells, NK cells, fibroblast) activated by m6A regulator and induces immunotherapy resistance for cancer cells. 3) Radiation induces m6a regulator and stabilizes mRNA of cancer stem cell. In the figure, the small upward black arrow indicates “upregulation” and the downward black arrow indicates “down regulation”.