Emerging Roles of Long Noncoding RNAs in Breast Cancer Epigenetics and Epitranscriptomics

Abstract

Breast carcinogenesis is a multistep process that involves both genetic and epigenetic changes. Epigenetics refers to reversible changes in gene expression that are not accompanied by changes in gene sequence. In breast cancer (BC), dysregulated epigenetic changes, such as DNA methylation and histone modifications, are accompanied by epitranscriptomic changes, in particular adenine to inosine modifications within RNA molecules. Factors that trigger these phenomena are largely unknown, but there is evidence for widespread participation of long noncoding RNAs (lncRNAs) that already have been linked to virtually any aspect of BC biology, making them promising biomarkers and therapeutic targets in BC patients. Here, we provide a systematic review of known and possible roles of lncRNAs in epigenetic and epitranscriptomic processes, along with methods and tools to study them, followed by a brief overview of current challenges regarding the use of lncRNAs in medical applications.

Keywords: RNA modifications; breast cancer; epigenetics; epitranscriptomics; long noncoding RNAs.

FIGURE 1

A schematic representation of two levels at which the reviewed modifications may occur along with the involved enzymes (a green box). (A) Epigenetic changes could involve chromosome remodeling, histone modifications and DNA methylation. (B) Epitranscriptomic changes, involve changes in mRNAs, tRNAs and lncRNAs, such as RNA editing, m6A modification and pseudouridilation.

FIGURE 2

LncRNA-mediated epigenetic modifications along with the involved enzymes (a green box). Chromatin remodeling may be affected by lncRNAs interacting with remodeling enzymes, such as PRC1 and PRC2. These modifications either enhance or suppress the activity of involved genes. Two types of histone modifications are shown here: histone methylation carried out by methyltransferases (in blue) and acetylation carried out by acetyltransferases (in green), both of which are subject to modulation by lncRNAs. Of note, lncRNAs involved in DNA methylation may either enhance or suppress the process.

FIGURE 3

LncRNA-mediated epitranscriptomic modifications. (A) A-to-I RNA editing in lncRNAs, may be triggered by their ability to form dsRNA structures. LncRNAs may also trigger A-to-I RNA editing in mRNAs by coming into direct interactions with them. Both A-to-I and C-to-U RNA editing could affect the coding potential and therefore influence the functions played by proteins. (B) m6A modification stabilizes RNAs, which is often associated with their increased cellular levels. In case of lncRNAs that act as miRNA sponges, after this type of methylation their functions may be affected, leading to increased levels of miRNAs. (C) Pseudouridilation (Ѱ) conducted by PUSs enzymes alters interactions between bases and often leads to changes in the structure of lncRNA and tRNA molecules, affecting their functions.