Transposable Elements in Human Cancer: Causes and Consequences of Deregulation

Abstract

Transposable elements (TEs) comprise nearly half of the human genome and play an essential role in the maintenance of genomic stability, chromosomal architecture, and transcriptional regulation. TEs are repetitive sequences consisting of RNA transposons, DNA transposons, and endogenous retroviruses that can invade the human genome with a substantial contribution in human evolution and genomic diversity. TEs are therefore firmly regulated from early embryonic development and during the entire course of human life by epigenetic mechanisms, in particular DNA methylation and histone modifications. The deregulation of TEs has been reported in some developmental diseases, as well as for different types of human cancers. To date, the role of TEs, the mechanisms underlying TE reactivation, and the interplay with DNA methylation in human cancers remain largely unexplained. We reviewed the loss of epigenetic regulation and subsequent genomic instability, chromosomal aberrations, transcriptional deregulation, oncogenic activation, and aberrations of non-coding RNAs as the potential mechanisms underlying TE deregulation in human cancers.

Keywords: cancer; epigenetics; genomic instability; non-coding RNAs; transposable elements.

Figure 1

Global loss of DNA methylation in cancer cells leads to TE reactivation. A common epigenetic feature in neoplastic cells is global demethylation, including within repeated sequences. Subsequently, TE reactivation can cause increasing somatic retrotransposition, non-coding RNA, and transcriptional deregulation. Red arrows show direct impacts of TE reactivation and black arrows show effects of retrotransposition.

Figure 2

Effects of retrotransposition on transcriptional deregulation. Insertion of TEs into (A) coding region can disturb or eliminate gene functions; (B) upstream of the gene loci can introduce a novel alternative promoter leading to the variation of protein products; (C) promoter region can disrupt cis-regulatory elements, as well as transcriptional start sites; (D) introns can introduce epigenetic remodeling events including DNA methylation and chromatin condensation, leading to gene silencing. At the post-transcriptional step, the introduction of TEs (E) in the introns can cause alternative splicing that causes various protein products and functions; (F) at the 3′UTR can introduce poly-adenylation sites leading to unstable mRNAs; and (G) at the 3′-UTR can create binding sites for miRNAs and other ncRNAs. Therefore, retrotransposition affects the efficiency of gene transcription and post-transcriptional regulation, and is associated with the deregulation of gene expression during human carcinogenesis.

Figure 3

TE-mediated carcinogenesis. Intra- and extracellular-mediated stresses lead to TE mobility through alterations of DNA methylation and chromatin remodeling. TE mobility might further induce and interconnect transcriptional deregulation, the activation of oncogenes, genomic instability, and ncRNA deregulation, to further contribute to human carcinogenesis. Arrows show causality and bidirectional arrows represent inter-correlation.