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.

Whole-Transcriptome Analysis of CD133+CD144+ Cancer Stem Cells Derived from Human Laryngeal Squamous Cell Carcinoma Cells

“…Autophagy plays crucial roles in cancer, recent study revealed that enhanced autophagic activity was detected in ovarian cancer stem cells, and inhibition of autophagy reduced chemoresistance and self-renewal [23]. Activated telomere maintenance mechanism allows prolonged survival of the cells, which considered as a hallmark of cancer cells [24]. Therefore, differentially expressed genes that enriched in these biological processes and pathways might be important contributors of the enhanced malignancy of LSCC stem cells.…”

Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas

“…For example, full-length LINE-1 elements (L1s, long interspersed nuclear elements-1) are repeat-rich intronic or intergenic (junk) sequences, and are transcribed as euchromatin RNAs (ecRNAs) that may play a role in chromosome structure and regulation by promoting a more open chromatin state [109]. L1s become inactivated early in development, while recent evidence indicates they can be activated in cancer [110,111], as well as neurodegeneration (reviewed in [112]) and during development in the brain (reviewed in [113,114]).…”

RNA as a fundamental component of interphase chromosomes: could repeats prove key?

“…Importantly, this abundant L1 RNA signal is from the numerous 5′ truncated L1s, distinct from the small number of full-length L1 elements capable of retrotransposition. Full-length L1s are inactivated early in development, although recent evidence indicates they can be activated in cancer [40,41], neurodegeneration (reviewed in: [42]) and during development in the mammalian brain ([43,44] reviewed in: [45,46]). However, this likely represents a separate phenomenon from the L1-rich Cot-1 ecRNA prevalent in all cells.…”