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Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M.

ABSTRACT: The human and Old World primate genomes possess conserved endogenous retrovirus sequences that have been implicated in evolution, reproduction, and carcinogenesis. Human endogenous retrovirus (HERV)-K with 5'LTR-gag-pro-pol-env-rec/np9-3'LTR sequences represents the newest retrovirus family that integrated into the human genome 1 to 5 million years ago. Although a high-level expression of HERV-K in melanomas, breast cancers, and teratocarcinomas has been demonstrated, the mechanism of the lineage-specific activation of the long terminal repeat (LTR) remains obscure. We studied chromosomal HERV-K expression in MeWo melanoma cells in comparison with the basal expression in human embryonic kidney 293 (HEK293) cells. Cloned LTR of HERV-K (HML-2.HOM) was also characterized by mutation and transactivation experiments. We detected multiple transcriptional initiator (Inr) sites in the LTR by rapid amplification of complementary DNA ends (5' RACE). HEK293 and MeWo showed different Inr usage. The most potent Inr was associated with a TATA box and three binding motifs of microphthalmia-associated transcription factor (MITF). Both chromosomal HERV-K expression and the cloned LTR function were strongly activated in HEK293 by transfection with MITF-M, a melanocyte/melanoma-specific isoform of MITF. Coexpression of MITF and the HERV-K core antigen was detected in retinal pigmented epithelium by an immunofluorescence analysis. Although malignant melanoma lines MeWo, G361, and SK-MEL-28 showed enhanced HERV-K transcription compared with normal melanocytes, the level of MITF-M messenger RNA persisted from normal to transformed melanocytes. Thus, MITF-M may be a prerequisite for the pigmented cell lineage-specific function of HERV-K LTR, leading to the high-level expression in malignant melanomas.

SUBMITTER: Katoh I

PROVIDER: S-EPMC3223611 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M.

Katoh Iyoko I Mírová Anna A Kurata Shun-ichi S Murakami Yasushi Y Horikawa Kenji K Nakakuki Natsuko N Sakai Takunobu T Hashimoto Kunihiko K Maruyama Ayako A Yonaga Takaaki T Fukunishi Nahoko N Moriishi Kohji K Hirai Hirohisa H

Neoplasia (New York, N.Y.) 20111101 11

The human and Old World primate genomes possess conserved endogenous retrovirus sequences that have been implicated in evolution, reproduction, and carcinogenesis. Human endogenous retrovirus (HERV)-K with 5'LTR-gag-pro-pol-env-rec/np9-3'LTR sequences represents the newest retrovirus family that integrated into the human genome 1 to 5 million years ago. Although a high-level expression of HERV-K in melanomas, breast cancers, and teratocarcinomas has been demonstrated, the mechanism of the lineag ...[more]

PMID: 22131883

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Project description:BackgroundLong non-coding RNAs (lncRNAs) are emerging as molecules that significantly impact many cellular processes and have been associated with almost every human cancer. Compared to protein-coding genes, lncRNA genes are often associated with transposable elements, particularly with endogenous retroviral elements (ERVs). ERVs can have potentially deleterious effects on genome structure and function, so these elements are typically silenced in normal somatic tissues, albeit with varying efficiency. The aberrant regulation of ERVs associated with lncRNAs (ERV-lncRNAs), coupled with the diverse range of lncRNA functions, creates significant potential for ERV-lncRNAs to impact cancer biology.MethodsWe used RNA-seq analysis to identify and profile the expression of a novel lncRNA in six large cohorts, including over 7,500 samples from The Cancer Genome Atlas (TCGA).ResultsWe identified the tumor-specific expression of a novel lncRNA that we have named Endogenous retroViral-associated ADenocarcinoma RNA or 'EVADR', by analyzing RNA-seq data derived from colorectal tumors and matched normal control tissues. Subsequent analysis of TCGA RNA-seq data revealed the striking association of EVADR with adenocarcinomas, which are tumors of glandular origin. Moderate to high levels of EVADR were detected in 25 to 53% of colon, rectal, lung, pancreas and stomach adenocarcinomas (mean = 30 to 144 FPKM), and EVADR expression correlated with decreased patient survival (Cox regression; hazard ratio = 1.47, 95% confidence interval = 1.06 to 2.04, P = 0.02). In tumor sites of non-glandular origin, EVADR expression was detectable at only very low levels and in less than 10% of patients. For EVADR, a MER48 ERV element provides an active promoter to drive its transcription. Genome-wide, MER48 insertions are associated with nine lncRNAs, but none of the MER48-associated lncRNAs other than EVADR were consistently expressed in adenocarcinomas, demonstrating the specific activation of EVADR. The sequence and structure of the EVADR locus is highly conserved among Old World monkeys and apes but not New World monkeys or prosimians, where the MER48 insertion is absent. Conservation of the EVADR locus suggests a functional role for this novel lncRNA in humans and our closest primate relatives.ConclusionsOur results describe the specific activation of a highly conserved ERV-lncRNA in numerous cancers of glandular origin, a finding with diagnostic, prognostic and therapeutic implications.

Dataset Information

Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M.

Publications

Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M.

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