The Reverse Transcriptase Encoded by LINE-1 Retrotransposons in the Genesis, Progression, and Therapy of Cancer

• Published in: Frontiers in chemistry Vol. 4; p. 6
• Main Authors: Sciamanna, Ilaria, De Luca, Chiara, Spadafora, Corrado
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.02.2016
• Subjects: cancer heterogeneity; Chemistry; differentiation therapy; epigenetics; LINE-1 retrotransposons; reverse transcriptase; tumorigenesis; tumorigenesis; differentiation therapy; LINE-1 retrotransposons; reverse transcriptase; cancer heterogeneity; epigenetics
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2016.00006

In higher eukaryotic genomes, Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons represent a large family of repeated genomic elements. They transpose using a reverse transcriptase (RT), which they encode as part of the ORF2p product. RT inhibition in cancer cells, either via RNA interference-dependent silencing of active LINE-1 elements, or using RT inhibitory drugs, reduces cancer cell proliferation, promotes their differentiation and antagonizes tumor progression in animal models. Indeed, the non-nucleoside RT inhibitor efavirenz has recently been tested in a phase II clinical trial with metastatic prostate cancer patients. An in-depth analysis of ORF2p in a mouse model of breast cancer showed ORF2p to be precociously expressed in precancerous lesions and highly abundant in advanced cancer stages, while being barely detectable in normal breast tissue, providing a rationale for the finding that RT-expressing tumors are therapeutically sensitive to RT inhibitors. We summarize mechanistic and gene profiling studies indicating that abundant LINE-1-derived RT can "sequester" RNA substrates for reverse transcription in tumor cells, entailing the formation of RNA:DNA hybrid molecules and impairing the overall production of regulatory miRNAs, with a global impact on the cell transcriptome. Based on these data, LINE-1-ORF2 encoded RT has a tumor-promoting potential that is exerted at an epigenetic level. We propose a model whereby LINE1-RT drives a previously unrecognized global regulatory process, the deregulation of which drives cell transformation and tumorigenesis with possible implications for cancer cell heterogeneity.