DNA methylation in pulmonary fibrosis and lung cancer

Abstract

Introduction: Pulmonary fibrosis is an age-related, progressive, and fatal disease with a median survival of 3-5 years after diagnosis; idiopathic pulmonary fibrosis (IPF) is the most common type. It is characterized by fibroblast proliferation and accumulation of excessive extracellular matrix. Patients with IPF are at increased risk for lung cancer. Epigenetic mechanisms are involved in lung fibrosis and cancer, and DNA methylation is critical in disease pathogenesis and progression. Therefore, studies of DNA methylation contribute to better understanding of the underlying mechanisms of these two respiratory diseases, and can offer novel diagnostic and treatment options.

Areas covered: This review discusses the latest advances in our understanding of epigenetic factors related to DNA methylation that impact development of lung cancer and pulmonary fibrosis, discusses the role of DNA methylation in promoting or inhibiting these diseases, and proposes its potential clinical significance in disease diagnosis and treatment.

Expert opinion: DNA methylation plays a critical role in lung cancer and fibrosis pathogenesis. DNA methylation offers a new biomarker for disease diagnosis or monitoring, and provides a new therapeutic target for treatment.

Keywords: Biomarkers; DNA methyl-binding protein; DNA methylation; DNA methyltransferases; epigenetic; idiopathic pulmonary fibrosis; lung cancer; pulmonary fibrosis.

Figure 1.. Idiopathic pulmonary fibrosis (IPF) and lung cancer have many similarities.

Lung cancer is classified into different subtypes, some of which are more frequently seen in IPF patients. There are many similarities between lung fibrosis and cancer. For example, high-risk factors for both diseases include aging, poor air, high-risk occupations, and smoking. IPF patients, especially with factors such as cigarette smoking and gender (male), are likely to develop lung cancer. These risk factors would alter DNA methylation status (hyper- or hypo-methylation), which would affect gene expression, and change the recruitment of methyl-binding proteins (MBD), and transcriptional factors (TF), which all contribute to the mechanisms underlying fibrogenesis and carcinogenesis. Altered DNA methylation can be targeted pharmacologically, used as diagnostic biomarkers, and used to monitor disease progression (see text for details).

Figure 2.. Classification of DNA methyltransferases (DNMTs) and Methyl-binding Proteins (MBPs).

A. DNMTs are classified as maintenance or de novo DNA methyltransferases. B. Three major families of MBPs. (i). The MBD family (all with MBD domain), including MeCp2, MBD1, MBD2, and MBD4 preferentially bind methylated DNA. (ii). Kaiso- and Kaiso-like proteins, shown with the main BTB domain and methyl-CpG-binding zinc fingers (mZF). Including Kaiso, ZBTB4, and ZBTB38. (iii). Set and Ring Finger-associated (SRA) domain, two members of UHRF1 and UHRF2 (Ubiquitin-like with PHD and RING finger domains 1 and 2). Ubl, ubiquitin-like domain; TTD, tandem tudor domain; PHD, plant homeodomain finger domain; SRA, SET, and RING-associated domain.