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Towards targeting transposable elements for cancer therapy

Nature Reviews Cancer volume 24, pages 123–140 (2024)Cite this article

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Abstract

Transposable elements (TEs) represent almost half of the human genome. Historically deemed ‘junk DNA’, recent technological advancements have stimulated a wave of research into the functional impact of TEs on gene-regulatory networks in evolution and development, as well as in diseases including cancer. The genetic and epigenetic evolution of cancer involves the exploitation of TEs, whereby TEs contribute directly to cancer-specific gene activities. This Review provides a perspective on the role of TEs in cancer as being a ‘double-edged sword’, both promoting cancer evolution and representing a vulnerability that could be exploited in cancer therapy. We discuss how TEs affect transcriptome regulation and other cellular processes in cancer. We highlight the potential of TEs as therapeutic targets for cancer. We also summarize technical hurdles in the characterization of TEs with genomic assays. Last, we outline open questions and exciting future research avenues.

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Fig. 1: Transposable element composition in the human genome.
Fig. 2: Tumour-suppressive and oncogenic effects of transposable elements in the cancer genome.
Fig. 3: Potential transposable-element-derived therapeutic targets.
Fig. 4: Technical challenges and contemporary algorithms in mapping transposable element expression.

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Acknowledgements

The authors thank members of the Wang laboratory for helpful discussions related to the project. Work performed in the Wang laboratory is supported by NIH grants R01HG007175, U24ES026699, U01HG009391 and UM1DA058219.

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  1. These authors contributed equally: Yonghao Liang, Xuan Qu, Nakul M. Shah.

Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA

    Yonghao Liang, Xuan Qu & Ting Wang

  2. Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, MO, USA

    Yonghao Liang, Xuan Qu & Ting Wang

  3. Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nakul M. Shah

  4. McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA

    Ting Wang

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Glossary

Alternative splicing

A cellular process whereby exons are joined differently to create alternative isoforms of the same gene that have different but related mRNA transcripts.

Antibody–drug conjugates

A rapidly developing class of therapeutic agents that combine monoclonal antibodies with drugs that can achieve cell-type-specific drug delivery.

A-to-I editing

A cellular process that is catalysed by adenosine deaminases acting on RNA (ADARs), which substitute an adenosine for an inosine on the mRNA molecule. Editing of protein-coding RNAs results in dramatic alterations to protein functions. Deficiencies in A-to-I editing lead to genetic diseases. However, the impact of A-to-I editing on Alu-element RNA sequences is still underexplored.

Bidirectional transcription

Transcription events that occur when there is one promoter on each side of a stretch of DNA sequence, initiating transcription over the sequence between the two promoters.

Cis-regulatory elements

DNA sequences that are binding sites for transcription factors and which modulate gene expression.

Condensate

Micrometre-scale subdomains within cells that concentrate biomolecules (such as transcription factors for specialized functions) but that are not bounded by membranes.

De novo transcript assembly

A computational process that utilizes transcriptomic data to construct transcript exon–intron structures.

DNase-hypersensitive sites

Chromatin regions that are characterized by elevated DNase I cleavage because of more accessible, local spatial distribution of nucleosomes.

Enhancers

Elements in the genome that enable the binding of activators and mediators that can subsequently activate expression of distal genes.

Exapted

An event in which a sequence evolves to a function that is different from the original function.

Insertional mutagenesis

Genetic mutations created by insertions of DNA segments, such as disruption of coding sequences of tumour-suppressor genes by LINE-1 retrotranspositions, that contribute to disease progression such as tumorigenesis.

Intergenic regions

DNA sequences located between genes that do not have coding potential. Parts of intergenic regions may contain functional regulatory elements.

Long non-coding RNA

RNA transcript more than 200 nucleotides in length that does not have translation potential. Long non-coding RNAs have a broad function in remodelling of chromatin structure, RNA splicing and stability, and in regulating protein functions by direct binding.

Long-read sequencing

Third-generation sequencing technology that can generate reads of thousands to hundreds of thousands of bases.

MHC tetramer

An important tool that consists of four major histocompatibility complex (MHC) molecules conjugated to a fluorochrome-labelled streptavidin to evaluate the stability of interactions between MHC molecules, antigens and T cell receptors. This tool helps to detect T cells that can recognize specific antigens.

Nanopore sequencing

One of the long-read sequencing platforms that obtains sequence information at single-molecule resolution by measuring the chemical kinetics of each base when passing each ultralong DNA molecule through a nanopore.

Neoantigens

Tumour-specific antigens presented on MHC complexes to trigger an immune response.

Promoters

A segment of DNA sequence that can be bound by RNA polymerase and other transcription machinery to initiate the process of gene expression.

Sense–antisense pairing

Complementary pairing of two nucleotide molecules.

Short-read sequencing

Also known as next-generation sequencing, short-read sequencing generates reads of hundreds of bases.

Splice acceptor sites

DNA sequences at the 3′ end of introns that terminate the intron and facilitate appropriate splicing.

Splice donor sites

DNA sequences at the 5′ end of introns that mark the beginning of introns and facilitate appropriate splicing.

Transcription-factor-binding sites

A stretch of DNA sequence that transcription factors bind to. Each transcription factor will have its own specific sequence pattern (motif) that it recognizes and binds to.

Trans-effects

Gene expression activity regulated by RNAs and proteins by binding to DNA sequences directly or indirectly.

V(D)J somatic recombination

A cellular process that occurs during the development of T cells and B cells that results in a highly diverse repository of T cell receptors and antibodies, respectively.

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Liang, Y., Qu, X., Shah, N.M. et al. Towards targeting transposable elements for cancer therapy. Nat Rev Cancer 24, 123–140 (2024). https://doi.org/10.1038/s41568-023-00653-8

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