N7-methylguanosine modification: from regulatory roles to therapeutic implications in cancer

Abstract

N7-methylguanosine (m7G) is one of the most common post-transcriptional epigenetic modifications. Different m7G methyltransferases (writers) load the m7G-cap at the 5'-terminal or inside the RNAs. For example, writers such as methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) and Williams-Beuren syndrome chromosome region 22 (WBSCR22) have been reported in mammals to promote cell proliferation, EMT, and chemoresistance in massive quantities of cancers. The underlying mechanism includes modulating the RNA secondary structure, preventing RNA degradation from exonucleases, and improving codon-dependent translation. However, some studies have shown that in colorectal and lung cancers, m7G inhibits tumor progression. m7G binding proteins (readers), such as eukaryotic translation initiation factor 4E (eIF4E), promote the efficiency of cap-dependent translation and accelerate the cell cycle to improve cancer progression. Due to the more profound understanding of m7G regulatory proteins in cancer, numerous studies aim to investigate the clinical efficiency of m7G-targeted therapy. eIF4E antisense oligonucleotide drug (4EASO) and Ribavirin are the most mature trials that competitively inhibit the binding of eIF4E to m7G-cap. These drugs have encouraging results in halting cancer progression and improving prognosis, including AML and non-small cell lung cancer, which provide a promising perspective for developing more m7G-targeted drugs. In the future, we look forward to an ongoing investigation into the role of m7G modification in tumors and drug resistance to m7G-related therapies to be solved. Therefore, the clinical application would be put into practice as soon as possible.

Keywords: N7-methylguanosine modification; RNA metabolism; cancer; cancer therapy.

Figure 1

Chemical structures of internal m7G modification and m7G-cap (Created with KingDraw).

Figure 2

The process and molecular functions of m7G modification in RNA metabolism. Different methyltransferases were essential for introducing internal m7G modification and cap m7G modification at 5’-termial in human, including METTL1/WDR4, RNMT/RAM, WBSC22 and TGS1, relative locations are marked with numbers. In the nucleus, m7G-cap could be recognized by CBC to generate RNA nuclear exportation. In the cytoplasm, the binding of TMG-cap and Snuportin1 associated with importin-β enables RNA to be imported into the nucleus. m7G regulates RNA degradation by maintaining RNA geometry structure and protecting RNAs from 5’ exonucleases and RTD pathway. m7G promotes RNA maturation by affecting secondary structures. m7G regulates mRNA translation through eIF4E recognition, interference of ribosome pausing and tRNA decoding.

Figure 3

The role of m7G regulators in human cancers. m7G regulators are associated with various kinds of cancers including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bladder cancer, prostate cancer, cervical cancer, glioblastoma, pancreatic cancer, acute myeloid leukemia, colon cancer, lung cancer, etc. The schema was prepared with object images from Servier Medical Art (https://smart.servier.com).