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LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines

Oncogene volume 35, pages 94–104 (2016)Cite this article

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Abstract

A hallmark of cancer cells is an activated telomere maintenance mechanism, which allows prolonged survival of the malignant cells. In more than 80% of tumours, telomeres are elongated by the enzyme telomerase, which adds de novo telomere repeats to the ends of chromosomes. Cancer cells are also characterized by expression of active LINE-1 elements (L1s, long interspersed nuclear elements-1). L1 elements are abundant retrotransposons in the eukaryotic genome that are primarily known for facilitating aberrant recombination. Using L1-knockdown (KD), we show for the first time that L1 is critical for telomere maintenance in telomerase-positive tumour cells. The reduced length of telomeres in the L1-KD-treated cells correlated with an increased rate of telomere dysfunction foci, a reduced expression of shelterin proteins and an increased rate of anaphase bridges. The decreased telomere length was associated with a decreased telomerase activity and decreased telomerase mRNA level; the latter was increased upon L1 overexpression. L1-KD also led to a decrease in mRNA and protein expression of cMyc and KLF-4, two main transcription factors of telomerase and altered mRNA levels of other stem-cell-associated proteins such as CD44 and hMyb, as well as a corresponding reduced growth of spheroids. The KD of KLF-4 or cMyc decreased the level of L1-ORF1 mRNA, suggesting a specific reciprocal regulation with L1. Thus, our findings contribute to the understanding of L1 as a pathogenicity factor in cancer cells. As L1 is only expressed in pathophysiological conditions, L1 now appears to be target in the rational treatment of telomerase-positive cancer.

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Acknowledgements

We want to thank Roger Reddel and Bert Vogelstein for providing cell lines, Silvia Bacchetti for adenovirus expressing hTERT, Satoru Kyo for hTERT promoter constructs. Furthermore, we appreciate the critical discussion with members of the Surgical Research Laboratories of the Medical University of Vienna, as well as with Igor Bondarev, Roger Reddel, Berthold Streubl and Wolfgang Köstler. Further, we appreciate the critical reading of the manuscript by Walter Berger and Christine Brostjan. SS and KH were supported by the Medical Scientific Fund of the Mayor of Vienna #10091.

Author Contributions

TA performed study plan, most of the experiments and data analysis. FE performed reporter gene assays and helped with all cell culture experiments. TA, FE, PK and SS performed real-time PCR experiments and cell cycle analysis. DM and MS helped with primer design for LINE-1 sequences, and stem cell gene expression analysis. BW helped with experimental design for TRAP-assays and telomere-specific Southern blot. KH helped with experimental design and provided use of adenoviruses. MB initiated, directed and supported the work through all levels of development. TA and MB wrote the manuscript that was revised by all the authors.

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Authors and Affiliations

  1. Department of Surgery, Cardiac Surgical Research Laboratories, Medical University of Vienna, Vienna, Austria

    T Aschacher & B Messner

  2. Department of Surgery, Surgery Research Laboratory, Medical University of Vienna, Vienna, Austria

    B Wolf, F Enzmann, P Kienzl & M Bergmann

  3. Department of Medicine I, Institute of Cancer Research, Vienna, Austria

    S Sampl & K Holzmann

  4. Department of Pathophysiology, Medical University of Vienna, Vienna, Austria

    M Svoboda & D Mechtcheriakova

  5. Comprehensive Cancer Center Vienna, Vienna, Austria

    D Mechtcheriakova, K Holzmann & M Bergmann

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  1. T Aschacher
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Aschacher, T., Wolf, B., Enzmann, F. et al. LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines. Oncogene 35, 94–104 (2016). https://doi.org/10.1038/onc.2015.65

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