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Inhibiting EZH2 Targets Atypical Teratoid Rhabdoid Tumor by Triggering Viral Mimicry via Both RNA and DNA Sensing Pathways [RNA-Seq]

ABSTRACT: Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213249 | GEO | 2024/09/05

REPOSITORIES: GEO

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Inhibiting EZH2 Targets Atypical Teratoid Rhabdoid Tumor by Triggering Viral Mimicry via Both RNA and DNA Sensing Pathways [CUT&RUN]

Project description:Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

2024-09-05 | GSE213248 | GEO

Epigenetic therapy induces transcription of Inverted SINEs and ADAR1 dependency

Project description:In this study we show that intronic and intergenic SINE elements, specifically inverted repeats (IR) Alus, are the major source of drug-induced immunogenic dsRNA. These IR-Alus are frequently located downstream of ‘orphan’ CpG Islands (CGIs). In mammals, the enzyme Adenosine Deaminases Acting on RNA (ADAR1) targets and destabilizes IR-Alu dsRNA, which prevents activation of MDA5. We found that ADAR1 establishes a negative feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Thus, epigenetic therapies trigger viral mimicry by inducing a subset of IR-Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising new strategy for cancer treatment.

2020-10-20 | GSE145639 | GEO

Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress

XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells

Project description:Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene (ISG) expression. XRN1 deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-b stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR, and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state.

2024-04-17 | GSE248036 | GEO

Targeting DHX9 triggers interferon response and replication stress in Small Cell Lung Cancer [RIP-Seq II]

Project description:Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry”, has emerged as an effective strategy to convert immunologically “cold” tumors into “hot”. Through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLCs). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other “cold” tumors where genomic instability contribute to pathology.

2024-02-01 | GSE247217 | GEO

Targeting DHX9 triggers interferon response and replication stress in Small Cell Lung Cancer [RIP-seq I]

2024-02-01 | GSE244104 | GEO

Targeting DHX9 triggers interferon response and replication stress in Small Cell Lung Cancer [RNA-seq]

2024-02-01 | GSE244103 | GEO

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [ADAR1KO HEK293T and WT MDA5]

Project description:Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral double-stranded RNA (dsRNA) sensor that induces antiviral immune response. We here demonstrate that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNA because its filament formation on dsRNA is impaired by the imperfect duplex structure, AGS-variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNA. Moreover, we identified an unexpected role of RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context-dependence of self vs. non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 to recognize dsRNA comes at a cost of self-recognition, and implicates a unique role of Alu RNAs as virus-like elements that shape the primate immune system.

2018-01-29 | GSE104864 | GEO

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [WT HEK293T and mutant MDA5]

2018-01-29 | GSE103539 | GEO

Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving Calcium-Calcineurin-NFAT signaling [EM-seq]

Project description:DNA methyltransferase inhibitors (DNMTi) are FDA-approved for various hematological malignancies but have limited efficacy in solid tumors. DNA hypomethylation with these drugs is associated with elevated lysine 27 tri-methylation on histone H3 (H3K27me3). We hypothesized that this EZH2-dependent repressive mark limits the full potential of DNMTi. Here, we show in cell line and tumoroid models of colorectal cancer, that low-dose DNMTi sensitizes cells to selective EZH2 inhibitors (EZH2i) that have limited single agent toxicity, and that EZH2i enhances DNMTi-driven molecular and therapeutic effects. Through integrative epigenomic analyses, we reveal that DNMTi induces H3K27me3 accumulation at genomic regions poised with EZH2. Unexpectedly, combined treatment alters the epigenome landscape to promote transcriptional upregulation of the Calcium-Calcineurin-NFAT signaling pathway. Blocking this pathway limits the transcriptional activating effects of the drug combination, including expression of transposable elements and innate immune response genes within a viral defense pathway. Consistently, we demonstrate positive correlations between DNMTi- and viral infection-associated transcription profiles and Calcium signal activation in colon cancer patient samples. Collectively, our study demonstrates that compensatory EZH2 activity following DNA hypomethylation presents a barrier to the therapeutic action of DNMTi in colon cancer, reveals a new application of EZH2i beyond cancers associated with PRC2 hyperactivity, and links Calcium-Calcineurin-NFAT signaling to epigenetic therapy-induced viral mimicry.

2024-02-26 | GSE237662 | GEO

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