Epigenetic silencing of multiple interferon pathway genes after cellular immortalization

Kulaeva, Olga I.; Drăghici, Sorin; Tang, Lin; Kraniak, Janice M.; Land, Susan; Tainsky, Michael A.

doi:10.1038/sj.onc.1206594

Cited by 127 publications

(133 citation statements)

References 46 publications

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“…The current challenge is to identify the molecular mediators of senescence, and determine how they are regulated in diverse oncogenic settings. IFN and ISGs are implicated in the senescent response (Kulaeva et al, 2003;Xin et al, 2004), and RNase-L is an established mediator of the antiproliferative activity of IFN (Hassel et al, 1993;Zhou et al, 1997), and functions as a tumor suppressor (Carpten et al, 2002;Casey et al, 2002); therefore, we examined the potential role for RNase-L in senescence.…”

Section: Discussionmentioning

confidence: 99%

“…A detectable increase in RNase-L was not observed in senescent cells (data not shown), suggesting that small, transient changes in RNase-L expression may be sufficient to initiate the senescence program. OAS is upregulated in senescence, and may function to activate RNase-L-induced senescence in the absence of changes in RNase-L expression (Kulaeva et al, 2003;Yoon et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Role of 2-5A-dependent RNase-L in senescence and longevity

Andersen

Judge

et al. 2006

Oncogene

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Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated b-galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wildtype fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L À/À mice survived 31.7% (Po0.0001) longer than strain-matched RNase-L +/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L À/À mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of 2-5A-dependent RNase-L in senescence and longevity

Andersen

Judge

et al. 2006

Oncogene

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“…Chronic subtoxic doses of stress-inducing compounds such as ethanol or H 2 O 2 can cause stress-induced senescence (Toussaint et al, 2002). Drug-induced senescence can be promoted by a variety of chemically and functionally unrelated DNA-damaging anticancer agents, such as doxorubicin (Chang et al, 1999), camptothecin (Han et al, 2002), 5-aza-2 0 -deoxycytidine (Timmermann et al, 1998;Kulaeva et al, 2003), aphidicolin (APH) and hydroxyurea (HU) (Yogev et al, 2006), or halogenated nucleotide analogs such as 5-bromo-2 0 -deoxyuridine (BrdU) (Michishita et al, 1999;Minagawa et al, 2005). Despite the fact that oncogenic or stress stimuli do not promote telomere shortening, prematurely senescent cells share similar characteristics with cells undergoing replicative senescence.…”

Section: Introductionmentioning

confidence: 99%

Cytokine expression and signaling in drug-induced cellular senescence

et al. 2009

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Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2 0 -deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon c (IFNc), IFNb and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/ chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNb-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.

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“…As a nucleoside analogue, 5-aza-2 0 -deoxycytidine (5-AZAdC) incorporates into DNA and covalently binds DNA methyltransferase l (DNMT1), thus inhibiting maintenance of DNA methylation and resulting in reexpression of epigenetically silenced genes (Herman and Baylin, 2003). Treatment of spontaneously immortal Li-Fraumeni fibroblasts with 5-AZAdC reactivated expression of 85 genes, 46% of which were ISGs (Kulaeva et al, 2003). Few studies, however, have examined functional consequences of epigenetic silencing of protein products of ISGs or their interacting ligands.…”

Section: Introductionmentioning

confidence: 99%

Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL

et al. 2007

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Human melanoma cell lines, SK-MEL-3 and SK-MEL-28, despite induction of the proapoptotic cytokine, Apo2L/TRAIL, did not undergo apoptosis in response to interferons . Postulating that genes important for apoptosis induction by IFNs might be silenced by methylation, the DNA demethylating agent 5-aza-2 0 -deoxycytidine (5-AZAdC) was assessed. DR4 (TRAIL-R1) was identified as one of the genes reactivated by 5-AZAdC with a >3-fold increase in 8 of 10 melanoma cell lines. Pretreatment with 5-AZAdC sensitized SK-MEL-3 and SK-MEL-28 cells to apoptosis induced by IFN-a2b and IFN-b; methylation-specific PCR and bisulfite sequencing confirmed demethylation of 5 0 CpG islands of DR4 and flow cytometry showed an increase in DR4 protein on the cell surface. In cells with reactivated DR4, neutralizing mAB to TRAIL reduced apoptosis in response to IFN-b or Apo2L/TRAIL. To further confirm the role of DR4, it was expressed by retroviral vector in SK-MEL-3 and SK-MEL-28 cells with reversal of resistance to IFN-b and Apo2L/TRAIL. Thus, reexpressing DR4 by 5-AZAdC or retroviral transfection in melanoma cell in which promoter methylation had suppressed its expression, potentiated apoptosis by IFNa2b, IFN-b and Apo2L/TRAIL. Reactivation of silenced proapoptotic genes by inhibitors of DNA methylation may enhance clinical response to IFNs or Apo2L/TRAIL.

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Epigenetic silencing of multiple interferon pathway genes after cellular immortalization

Cited by 127 publications

References 46 publications

Role of 2-5A-dependent RNase-L in senescence and longevity

Role of 2-5A-dependent RNase-L in senescence and longevity

Cytokine expression and signaling in drug-induced cellular senescence

Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL

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