• Modification of RNA N6 methyladenosine for cancer treatment
  • Mohaddese Gafourifard,1 Sana Falahi,2 faezeh Hemmati,3 Sepideh Asadi,4 Zahra Babaei,5 Maghsood Mehri,6,*
    1. BSc student of Medical Laboratory Sciences, Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran
    2. BSc student of Medical Laboratory Sciences, Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran.
    3. BSc student of Medical Laboratory Sciences, Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran.
    4. BSc student of Medical Laboratory Sciences, Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran.
    5. BSc student of Medical Laboratory Sciences, Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran.
    6. Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran.


  • Introduction: Cancer has become a serious threat to human health, but its treatment faces many obstacles. N6-methyladenosine (m6 A) is the most common internal modification of eukaryotic mRNA. It modulates immune cell activation and microenvironmental (TME) infiltration and thus may affect the efficacy of immunotherapy. Abnormal regulation of m6A changes is essential for tumorigenesis, progression, invasion, metastasis, and apoptosis of a malignant tumor. Methylation modification at the 6th nitrogen atom of adenine that is dynamic and reversible. m6A is regulated by methylases ("writers") and demethylases ("erasers") and recognized and processed by m6A-binding proteins ("readers"), which further regulate the transport, localization, translation, and degradation of m6A RNA. This increases the expression of an oncogene or decreases the expression of a tumor suppressor gene and may become a therapeutic target for the malignancies that are the subject of this review
  • Methods: For the subsequent systematic review, the necessary data were collected, where possible, using the keywords and MeSH (medical title) terms listed below, as well as cross-referencing key databases such as PubMed, Science Direct and ProQuest. Additionally, a manual search was performed using Google Scholar to increase the sensitivity of the search. The statistical survey population includes all contextual studies conducted between January 2018 and January 2023. After reviewing the relevant results and assessing the quality of the pieces of evidence, 14 articles in English were reviewed
  • Results: Intrinsic modification of m6A regulates tumor cell fate by targeting specific genes in different cancer types. m6A readers such as YTHDF1 etc. indicate that these reader proteins are primarily intended to alter protein-RNA interactions by altering m6A homologous binding to RNA-binding proteins and RNA secondary structure. For example, impairment of YTHDF1 in gastric cancer progression results progression and poor prognosis. m6A methyltransferase includes methyltransferase 3 (METTL3), METTL14, WTAP, etc. also known as writer. Its primary function is to catalyze the m6A modification of adenylate on mRNA. All of these methyltransferases play an important role in the formation of METTL3-METTL14 complexes in various cells and influence tumor cell proliferation and migration. The study discovered four small molecules that can increase the activity of this complex. The reversibility of m6A modifications is due to demethylases such as FTO, the first demethylase discovered. the founded about how modification of m6A regulates the antitumor functions of immune cells: m6A writer METTL3 and reader YTHDF2 enhance the antitumor immunity of natural killer cells METTL3 and YTHDF2. METTL3-mediated modification of m6A leads to the activation and maturation of dendritic cells and causes them to present new antigens and thus activate T cells. Reduction of METTL3 in CD4+ T cells disrupts cellular homeostasis and cell differentiation and negatively regulates STAT5 activation via IL -7/suppressor Signaling cytokines (SOCS). Reduction of METTL3 inhibits Treg cell function and stability by inhibiting IL-2/STAT5 signaling and promotes cytokine secretion by effector T cells. This leads to an increase in the antitumor immune response in TME. Therefore, targeted modifications of m6A should: 1) inhibit tumor cell growth directly, 2) increase the antitumor potential of immune cells, e.g. increasing cytotoxicity of CD8+ T cells and NK cells, 3) remodel TME by reprogramming M2 TAM into M1 TAM.
  • Conclusion: Gradually, m6A emerged as an important epigenetic modification with reversible properties, an enzyme system associated with the modification, and a role in various disease processes. It offers unlimited possibilities for later diagnosis and treatment of cancer. Writers can catalyze the installation of m6A onto RNA, while erasers can remove these changes. Finally, reader recognition of m6A methylation affects splicing, export, degradation, translation, and other biological processes of mRNA.m6A seems to act as a double-edged sword in cancer. Some genes can promote tumor growth when methylated, while others, if methylation is suppressed, can promote tumor growth. For example, in CRC, SOX2 has a cancer-promoting role via METTL3-catalyzed methylation, while in breast cancer, BNIP3 has a cancer-promoting role via FTO-catalyzed demethylation. It is expected that these modified m6A molecules will become powerful markers for early cancer diagnosis and prognosis as well as potential therapeutic targets, thus providing new insights for cancer diagnosis and treatment.
  • Keywords: N6-methyladenosine, m6A methylation, neoplasms therapeutics, cancer immunotherapy