LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond

Abstract

DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development.

Keywords: Cancer; DNA methylation; DNMT; Non-coding RNA; TET; lncRNA.

Fig. 1

LncRNA interacts with DNMTs/TETs. a. LncRNAs directly recruit DNMTs/ TETs. b. LncRNAs indirectly recruit DNMTs via EZH2/PHB2. c. LncRNAs indirectly recruit TETs via GADD45A. d. LncRNAs sequestrate DNMTs

Fig. 2

LncRNAs regulate DNMT activity via nucleocytoplasmic shuttling. LncRNA CCDC26 interacts with DNMT1 and promotes its localization from the cytosol to the nucleus. LncRNA NKILA sequesters NF-κB in the cytoplasm, which hinders NF-κB recruitment of DNMT3A in the nucleus

Fig. 3

LncRNAs control SAM/SAH level to regulate DNMT activity. S-adenosylhomocysteine (SAM) is biosynthesized by MAT (methionine adenosyltransferase) and converted to SAH (S-adenosylhomocysteine) by DNMTs. SAH is also a strong feedback inhibitor of DNMTs and it can be cleaved by S-adenosylhomocysteine hydrolase (SAHH). LncRNAs control SAM/SAH level by interacting with MAT or SAHH, and carcinogens such as benzo [a]pyrene (BaP) might enhance the interaction

Fig. 4

LncRNAs regulate the expression of DNMTs/ TETs at diverse levels. Firstly, lncRNAs might regulate the transcription of DNMTs via interaction with EZH2 to form repressive chromatin; Secondly, lncRNAs can stabilize DNMTs mRNA by recruiting HuR or as a miRNA sponge; Thirdly, lncRNAs regulate DNMT on the protein level by promoting or inhibiting its ubiquitination

Fig. 5

Potential therapeutic strategies for lncRNA targeting based on lncRNA- mediated DNA methylation. The middle panel shows the interaction between lncRNA and DNA methylation regulators, which could be specifically interrupted by small molecular compounds (right panel). Alternatively, the regulators could also be modulated by lncRNA mimics (left panel)