title: LINE-1 induces hTERT and ensures telomere maintenance in tumour cell lines.
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.
authors: Cardiac Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: T
authors: T
authors: Aschacher
authors: Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: B
authors: B
authors: Wolf
authors: Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: F
authors: F
authors: Enzmann
authors: Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: P
authors: P
authors: Kienzl
authors: Cardiac Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: B
authors: B
authors: Messner
authors: Department of Medicine I, Institute of Cancer Research, Vienna, Austria.
authors: S
authors: S
authors: Sampl
authors: Department of Pathophysiology, Medical University of Vienna, Vienna, Austria.
authors: M
authors: M
authors: Svoboda
authors: Department of Pathophysiology, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors: D
authors: D
authors: Mechtcheriakova
authors: Department of Medicine I, Institute of Cancer Research, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors: K
authors: K
authors: Holzmann
authors: Surgery Research Laboratory, Department of Surgery, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Vienna, Austria.
authors: M
authors: M
authors: Bergmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D061985:Madin Darby Canine Kidney Cells; D008546:Melanoma, Experimental; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C494023:L1 ORF1 protein, human; C494024:L1 ORF2 protein, human; D012261:Ribonucleoproteins; D012194:RNA-Directed DNA Polymerase; C509186:TERT protein, human; D019098:Telomerase; D004720:Endonucleases