Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli, Katherine B.; Strissel, Pamela L.; Desrichard, Alexis; Li, Huili; Henke, Christine; Akman, Benjamin; Hein, Alexander; Rote, Neal S.; Cope, Leslie; Snyder, Alexandra; Makarov, Vladimir; Budhu, Sadna; Slamon, Dennis J.; Wolchok, Jedd D.; Pardoll, Drew M.; Beckmann, Matthias W.; Zahnow, Cynthia A.; Merghoub, Taha; Chan, Timothy A.; Baylin, Stephen B.; Strick, Reiner

doi:10.1016/j.cell.2015.07.011

Cited by 1,480 publications

(1,470 citation statements)

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“…These elevated dsRNA species were mostly found in introns, corroborating known transcriptome‐wide HNRNPC binding regions (Konig et al , 2010; Zarnack et al , 2013). This differs from previous observation of elevated dsRNA derived from normally hypermethylated endogenous retroviruses (ERVs) that are activated by anti‐tumor inhibitors to trigger the IFN response as a therapeutic approach (Chiappinelli et al , 2015; Roulois et al , 2015; Goel et al , 2017). Heterogeneous nuclear ribonucleoprotein C is well known for its function in regulating RNA splicing by binding with introns, especially the introns containing Alu (Konig et al , 2010; Zarnack et al , 2013).…”

Section: Introductioncontrasting

confidence: 84%

“…However, in our work done in different types of breast cancer cells, expression profiles of the down‐stream genes indicated that NOTCH3 signaling was not amplified when interferon signaling was activated. On the other hand, several other studies have reported that up‐regulated dsRNA from endogenous retrovirus (ERV) in tumor cells, triggered by DNA methyltransferase inhibitors or CDK4/6 inhibitors, induced IFN responses and thus inhibited tumor development (Chiappinelli et al , 2015; Roulois et al , 2015; Goel et al , 2017). Our proposed model is similar to these studies, even though the dsRNA species in our study were originated from a different resource than ERV.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies showed transcriptional activations of the ERVs triggered by several anti‐tumor drugs, which in turn resulted in ERV‐originated dsRNA accumulation, potent interferon responses, and significant tumor inhibition (Chiappinelli et al , 2015; Roulois et al , 2015; Goel et al , 2017). In contrast, our study showed that upon perturbation of the RBP HNRNPC, the non‐ERV pre‐mRNA introns gave rise to dsRNA, which triggered the interferon response and tumor growth arrestment as well.…”

Section: Discussionmentioning

confidence: 99%

“…These interferon responses have been shown to be involved in regulating tumor development due to its well‐characterized pro‐apoptotic and anti‐proliferative effects in various types of cancer cells, including myeloma cell lines (Chen et al , 2001), lymphoma (Yang et al , 2013), liver cancer cells (Maeda et al , 2014; Murata et al , 2006; Sangfelt et al , 1997), and sarcoma cell lines (Sanceau et al , 2000). In fact, recent studies have shown that the IFN response triggered by endogenous dsRNA plays a central role in executing the therapeutic effects of anti‐tumor drugs such as DNA methyltransferase inhibitors and CDK4/6 inhibitors in multiple types of cancer (Chiappinelli et al , 2015; Roulois et al , 2015; Goel et al , 2017). …”

Section: Introductionmentioning

confidence: 99%

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Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

et al. 2018

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Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG‐I was responsible for such tumor‐inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double‐stranded RNA (dsRNA), the binding ligand of RIG‐I. These up‐regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre‐mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well‐characterized endogenous retroviruses that encode dsRNA. In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down‐stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.

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Section: Introductioncontrasting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

et al. 2018

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“…14 Mechanistically, it Chiappinelli et al demonstrated that DNMTi induce a type I interferon (IFN) response due to viral mimicry. 15 Moreover, enhanced anti-tumor immunity by combining DNMTi with HDACi involves type I IFN, MYC depletion and profound alterations in the tumor microenvironment. 9,10 …”

Section: Introductionmentioning

confidence: 99%

Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

et al. 2018

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Immune evasion is an important driver of disease progression in the plasma cell malignancy multiple myeloma. Recent work highlights the potential of epigenetic modulating agents as tool to enhance anti-tumor immunity. The immune modulating effects of the combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor in multiple myeloma is insufficiently characterized. Therefore, we used the murine immunocompetent 5T33MM model to investigate hallmarks of immunogenic cell death as well as alterations in the immune cell constitution in the bone marrow of diseased mice in response to the DNA methyltransferase inhibitor decitabine and the histone deacetylase inhibitor quisinostat. Vaccination of mice with 5T33 cells treated with epigenetic compounds delayed tumor development upon a subsequent tumor challenge. In vitro, epigenetic treatment induced ecto-calreticulin and CD47, as well as a type I interferon response. Moreover, treated 5T33vt cells triggered dendritic cell maturation. The combination of decitabine and quisinostat in vivo resulted in combinatory anti-myeloma effects. In vivo, epigenetic treatment increased tumoral ecto-calreticulin and decreased CD47 and PD-L1 expression, increased dendritic cell maturation and reduced CD11b positive cells. Moreover, epigenetic treatment induced a temporal increase in presence of CD8-positive and CD4-positive T cells with naive and memory-like phenotypes based on CD62L and CD44 expression levels, and reduced expression of exhaustion markers PD-1 and TIM3. In conclusion, a combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor increased the immunogenicity of myeloma cells and altered the immune cell constitution in the bone marrow of myeloma-bearing mice.

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All I's on the RADAR: role of ADAR in gene regulation

Shevchenko

Morris

2018

FEBS Letters

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Adenosine to inosine (A-to-I) editing is the most abundant form of RNA modification in mammalian cells, which is catalyzed by adenosine deaminase acting on the double-stranded RNA (ADAR) protein family. A-to-I editing is currently known to be involved in the regulation of the immune system, RNA splicing, protein recoding, microRNA biogenesis, and formation of heterochromatin. Editing occurs within regions of double-stranded RNA, particularly within inverted Alu repeats, and is associated with many diseases including cancer, neurological disorders, and metabolic syndromes. However, the significance of RNA editing in a large portion of the transcriptome remains unknown. Here, we review the current knowledge about the prevalence and function of A-to-I editing by the ADAR protein family, focusing on its role in the regulation of gene expression. Furthermore, RNA editing-independent regulation of cellular processes by ADAR and the putative role(s) of this process in gene regulation will be discussed.

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Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Cited by 1,480 publications

References 92 publications

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

All I's on the RADAR: role of ADAR in gene regulation

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