Abstract 3870: Telomeric non-coding RNA causes genome-wide alteration of gene expression in cancer

Abstract

Abstract The end replication problem of linear chromosome DNA causes telomere shortening and eventual senescence of normal cells. Cancer cells reactivate telomerase to maintain their telomere length and exhibit an infinite replicative potential. However, telomerase activation does not necessarily increase the average telomere length in cancer cells. Actually, cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. We previously demonstrated that forced telomere elongation in cancer cells promotes their differentiation in a xenograft tumor and represses innate immune genes that are upregulated in various human cancers. This implies that short telomeres of cancer cells contribute to their malignancy. However, it is completely unknown how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated human cancer cells. Using three different cancer cell lines, including those from prostate, breast and stomach, we found that telomere elongation by hTERT overexpression up-regulates TERRA signals, which were detected by northern blot analysis, and down-regulates innate immune genes such as STAT1, ISG15, and OAS3 in vivo. These changes were caused by telomere elongation and not by enhanced telomerase activity or hTERT overexpression per se. Down-regulation of the innate immune genes was also observed in the telomere-elongated cells under three-dimensional (3D) culture conditions, which mimicked the tumor microenvironment in vivo. Introduction of TERRA oligonucleotides repressed the innate immune genes even in cells with short telomeres under 3D culture conditions. Intriguingly, this gene repression appeared to occur from the action of the non-canonical nucleic acid structure called G-quadruplex (G4) in TERRA, because non-telomeric (i.e., non-G4-forming) control oligonucleotides had no effect whereas another non-telomeric but G4-forming oligonucleotide phenocopied the TERRA oligonucleotides. Transcriptome analysis revealed that telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various human cancers. Taken together, these observations suggest that the telomeric non-coding RNA G4 counteracts cancer malignancy through suppression of innate immune genes, and give a new insight into our understanding of telomere shortening in human cancer. Citation Format: Kyotaro Hirashima, Hiroyuki Seimiya. Telomeric non-coding RNA causes genome-wide alteration of gene expression in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3870. doi:10.1158/1538-7445.AM2015-3870