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Oncogene. 2016 Jan 7;35(1):94-104. doi: 10.1038/onc.2015.65. Epub 2015 Mar 23.

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

Author information

1
Cardiac Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
2
Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
3
Department of Medicine I, Institute of Cancer Research, Vienna, Austria.
4
Department of Pathophysiology, Medical University of Vienna, Vienna, Austria.
5
Comprehensive Cancer Center Vienna, Vienna, Austria.

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.

PMID:
25798839
DOI:
10.1038/onc.2015.65
[Indexed for MEDLINE]

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