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Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [RNA-seq]

ABSTRACT: Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [RNA-seq]

PROVIDER: PRJNA976351 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24741716_1.fastq.gz	Fastqsanger.gz
	SRR24741716_2.fastq.gz	Fastqsanger.gz
	SRR24741717_1.fastq.gz	Fastqsanger.gz
	SRR24741717_2.fastq.gz	Fastqsanger.gz
	SRR24741718_1.fastq.gz	Fastqsanger.gz

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Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [RNA-seq]

Project description:Cancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 depletion increased the sensitivity of HNSCC cancer cells to IFN-β, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 binds to and regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain-Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1 and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the promoters and/or gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC and poor response to neoadjuvant pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.

2023-05-26 | GSE233494 | GEO

Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [ChIP-seq]

2023-05-26 | GSE233168 | GEO

Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

Project description:Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

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Smyd3-mediated immuno-modulation in HPV-negative head and neck squamous cell carcinoma mouse models.

Project description:SET and MYND-domain containing protein 3 (SMYD3) mediates epigenetic repression of type I IFN response genes in human papilloma virus (HPV)-negative HNSCC cells, and Smyd3 depletion using anti-sense oligonucleotides (ASOs) increases the sensitivity of syngeneic mouse oral carcinoma (MOC1) models to anti-PD-1 therapy. In this study, we interrogated the effects ASO-induced Smyd3 depletion in the cancer and immune cell populations, as well as the global changes in the tumor microenvironment (TME) of MOC1 tumors treated with Smyd3 ASOs and anti-PD-1. Single-cell RNA-seq of MOC1 tumors treated with Smyd3 ASOs revealed enrichment of type I IFN response pathways in cancer cells, a shift of CD8+ T-cells towards an activated/memory phenotype and a shift of neutrophils towards an anti-tumorigenic phenotype. While Smyd3 ASOs seemed to also promote a Treg and M2 macrophage phenotype, bulk RNA-seq of MOC1 tumors treated with Smyd3 ASOs and anti-PD-1 revealed enrichment of type I IFN response pathways and upregulation of CD8+ T-cell attracting chemokines, implying the induction of an inflamed TME. Non-responder MOC1 tumors to the Smyd3 ASO and anti-PD-1 combination revealed mechanisms of resistance derived from cancer cells, macrophages and CD8+ T-cells, including neutrophil enrichment through upregulation of Cxcl2, repression of Cxcl9 and defective antigen presentation. This study sheds light in the immunomodulatory functions of Smyd3 in an in vivo setting and provides insight into actionable mechanisms of resistance to improve the therapeutic efficacy of Smyd3 ASO and anti-PD-1 combination treatment.

2024-10-10 | GSE273232 | GEO

Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [ChIP-seq]

Project description:Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [ChIP-seq]

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SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

Project description:Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.

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Smyd3-mediated immuno-modulation in HPV-negative head and neck squamous cell carcinoma mouse models.

Project description:Smyd3-mediated immuno-modulation in HPV-negative head and neck squamous cell carcinoma mouse models.

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RNA-seq of HN-6 (control) and 5-3 (SMYD3 KO) cell lines.

Project description:We used RNA-seq to evaluate the transcriptomic changes induced by permanent SMYD3 KO in the HPV-negative head and neck squamous cell carcinoma cell lines HN-6.

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scRNA-sequencing from HPV-positive head and neck squamous cell carcinomas

Project description:We report single cell transcriptome data from HPV-positive head and neck squamous cell carcinoma patients

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Genome-wide mapping of human SMYD3 and H3K4me3 in the HN-6 (control) and 5-3 (SMYD3 KO) HPV-negative head and neck squamous cell carcinoma cell line.

Project description:We used CUT&RUN to evaluate the genome-wide mapping of human SMYD3 and H3K4me3 in HN-6 and 5-3 (SMYD3 KO) cells.

2024-11-01 | GSE280252 | GEO