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Menéndez, Laura; Benigno, Benedict B.; McDonald, John F.

doi:10.1186/1476-4598-3-12

Cited by 114 publications

(43 citation statements)

References 30 publications

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“…Chromosome deletions and translocations probably caused by retrotransposition events have indeed been observed in several human cancers (Morse et al, 1988;Nagarajan et al, 1990;Miki et al, 1992;Pomykala et al, 1994;Liu et al, 1997). Moreover, a significant increase in the expression of a variety of retrotransposons and direct evidence for the hypomethylation of L1s has been observed during human cellular transformation (Takai et al, 2000;Menendez et al, 2004;Suter et al, 2004). …”

Section: Discussionmentioning

confidence: 97%

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

et al. 2005

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Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencing of retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronicphase (CP, n ¼ 140) and the blast crisis (BC, n ¼ 47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (Po0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (Po0.0001) and c-MET gene antisense transcription (Po0.0001), and was significantly associated with high levels of BCR-ABL (P ¼ 0.02) and DNMT3b4 (P ¼ 0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P ¼ 0.004) or imatinib (P ¼ 0.034) and progression-free survival (P ¼ 0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML.

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Section: Discussionmentioning

confidence: 97%

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

et al. 2005

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“…HERV-K is thought to be transcriptionally silent in normal cells, and becomes active after malignant transformation (8,11), except in the case of brain tumors (12). Increased expression of HERV-K has been detected in human cancers (8,13–21), and transcripts of HERVs have been detected by many independent investigators in various types of cancer that include breast cancer (8,22,23), ovarian cancer (24, 25), lymphoma (26,27), melanoma (11,28–32), germ line tumors (33–35), and prostate cancer (5, 36). Our laboratory showed that the HERV-K family is active and overexpressed in breast cancer (2,23,37–40): HERV-K expression was detected in 45% to 93% of primary breast tumors (N=479), and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Radvanyi

Yin

et al. 2017

Clinical Cancer Research

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Purpose We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer (PC). Experimental Design shRNA was employed to knockdown (KD) the expression of HERV-K in PC cells. Results HERV-K env expression was detected in seven PC cell lines and in 80% of PC patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several PC cell lines. RT activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in PC patient sera (N=106) than in normal donor sera (N=40). Importantly, the in vitro and in vivo growth rates of three PC cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several PC cells or tumors. Conclusion These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in PC. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of PC, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis and immunotherapy of PC.

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“…Likely, the hypomethylation observed in frail subjects can be associated to an accentuated deficiency to achieve the remethylation after DNA replication that, as reported in Gravina and Vijg (2010), occurs during aging. In addition, the above hypomethylation could derepress silenced retrotransposons, such as L1 or IAP, thus inducing genome instability that might account for the decline typical of frailty status (Barbot et al 2002;Menendez et al 2004;Maslov and Vijg 2009). Moreover, longitudinal data provide an important contribution to studies which consider frailty as a dynamic process.…”

Section: Discussionmentioning

confidence: 96%

Global DNA methylation in old subjects is correlated with frailty

Bellizzi

D’Aquila

Montesanto

et al. 2011

AGE

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Epigenetic variations have been widely described to occur during the aging process. To verify if these modifications are correlated with the inter-individual phenotypic variability of elderly people, we searched for a correlation between global DNA methylation levels and frailty. We found that the global DNA methylation levels were correlated to the frailty status in middle/advanced-aged subjects but not with age. A 7-year follow-up study also revealed that a worsening in the frailty status was associated to a significant decrease in the global DNA methylation levels. These results suggest that the relaxation of the epigenetic control in aging is specifically associated with the functional decline rather than with the chronological age of individuals. Thus, the modifications of DNA methylation, representing a drawbridge between the genetic and the environmental factors affecting the age-related decay of the organism, may play an important role in determining physiological changes over old age.

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Cited by 114 publications

References 30 publications

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Global DNA methylation in old subjects is correlated with frailty

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