Emerging role of N6-methyladenosine RNA methylation in lung diseases

Abstract

In recent years, with the increase of air pollution, smoking, aging, and respiratory infection, the incidence rate and mortality of lung diseases are increasing annually, which has become a major hazard to human health. N6-methyladenosine (m6A) RNA methylation is the most abundant modifications in eukaryotes, and such modified RNA can be specifically recognized and combined by m6A recognition proteins and then mediate RNA splicing, maturation, enucleation, degradation, and translation. More and more studies have revealed that the m6A modification is involved in the pathogenesis and development of some diseases; however, the mechanisms of m6A in lung diseases are poorly understood. In this review, we summarize the latest progress in the biological function of m6A modifications in lung diseases and discuss the potential therapeutic and prognostic strategies. The dysregulation of global m6A levels and m6A regulators may affect the occurrence and development of asthma, chronic obstructive pulmonary disease, lung cancer, and other lung diseases through inflammation and immune function. In lung cancer, this modification has an important impact on malignant cell proliferation, migration, invasion, and drug resistance. In addition, abnormally changed m6A-modified proteins in lung cancer tissue samples and circulating tumor cells (CTCs) may be used as diagnostic and prognostic markers of lung cancer. Models composed of multiple m6A regulators can be used to evaluate the risk prediction or prognosis of asthma and pulmonary fibrosis. In general, the in-depth study of m6A modifications is a frontier direction in disease research. It provides novel insights for understanding of the molecular mechanisms underlying disease occurrence, development, and drug resistance, as well as for the development of effective novel therapeutics.

N6-methyladenosine reader YTHDF1 regulates the proliferation and migration of airway smooth muscle cells through m6A/cyclin D1 in asthma

“…Currently, the pathophysiology of asthma is complex, including airway remodeling and inflammatory cells invasion and so on. Airway remodeling refers to a series of structural changes in airway structure in patients with asthma, including epithelial injury, increased basement membrane thickness, airway smooth muscle thickening, goblet cell metaplasia, and airway vascular and lymphatic proliferation ( Xu et al, 2022 ). This study unveiled a novel finding that m 6 A reader YTHDF1 play acritical role in asthma airway remodeling, involving ASMCs proliferation and migration abilities.…”

“…N 6 -methyladenosine (m 6 A) is the most abundant modification in mRNA, which is regulated by m 6 A methyltransferases, demethylases and readers. In the respiratory diseases, there are more and more literature reveal the important functions of m 6 A via variety of evidence ( Xu et al, 2022 ). For instance, m 6 A writer METTL3 is up-regulated in PM2.5 exposured mice lung injury and METTL3 up-regulated the m 6 A modification of Interleukin 24 (IL24) through via METTL3/YTHDF1-coupled epitranscriptomal regulation ( He et al, 2022 ).…”

RNA modifications in pulmonary diseases

“…Respiratory diseases, particularly lung cancer, have been frequently linked to RNA modifications in numerous reports. [16][17][18] Lung cancer, as of 2020, emerged as the second most common malignancy globally, representing 11.4% of all new cancer diagnoses and standing as the primary contributor to cancer-related deaths, claiming 1.8 million lives annually (18%). 113 It is well accepted that one of the significant hallmarks of cancer is the aberrant expression of genes, which is linked to the accumulation of genetic and epigenetic changes driving the occurrence and progression of human cancers.…”

“…Despite previous explicit reviews discussing different regulators associated with m 6 A modification in lung cancer, [15][16][17][18] our review provides a systematic overview. Linked to the activation of lung cancer-related signaling pathways are the various signaling pathways associated with m 6 A methylation, the most abundant RNA modification in eukaryotic cells.…”

“…14 A plethora of studies have consolidated findings on the interplay between RNA modifications and PDs, with specific attention directed toward lung cancer. [15][16][17][18] Moreover, considerable attention has been devoted to investigating the link between RNA modifica-F I G U R E 1 Epigenetic modifications in pulmonary diseases. Pulmonary diseases are short for a variety of complex lung injuries, including lung cancer, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, acute respiratory distress syndrome (ARDS), and pulmonary tuberculosis (PTB), which can be triggered by multiples of factors like particulate and gas inhalation, allergen stimulation, pathogen invasion (viruses, bacteria and fungi), abnormal immunity, and inflammation.…”