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| Status |
Public on May 26, 2023 |
| Title |
Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
For samples VS427, VS435-VS440, VS409-VS415 and VS669-VS674, HN-6 (parental control cells) and 5-3 cells (SMYD3 KO cell line) were exposed to human IFN-β for 24h prior to collection. For VS531 and VS539-VS544, HN-6 cells were transfected with control or SMYD3 targeting siRNAs for 72h and exposed to human IFN-β for 24h prior to collection. Three biological replicates were generated per condition. Cells were then processed using CUT&RUN assays targeting SMYD3 (Abcam 187149), H3K4me3 (EpiCypher, 13-0041) and H4K20me3 (ThermoFisher, MA5-36090).
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| Contributor(s) |
Vassiliki S, Nupur N, Benjamin B, Samantha S, Sohyoung K, Mohd Saleem D |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
May 22, 2023 |
| Last update date |
May 27, 2023 |
| Contact name |
Vinutha Balachandra |
| Organization name |
National Institute for Health
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| Department |
National Cancer Institute, Genetics Branch
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| Lab |
Yeast Genome Stability Section
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| Street address |
10 Center Drive
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
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| Samples (26)
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| GSM7405576 |
HN-6, H4K20me3, rep3, CS029758 [VS437] |
| GSM7405577 |
5-3, H4K20me3, rep1, CS029758 [VS438] |
| GSM7405578 |
5-3, H4K20me3, rep2, CS029758 [VS439] |
| GSM7405579 |
5-3, H4K20me3, rep3, CS029758 [VS440] |
| GSM7405580 |
HN-6, negative control, rep1 [VS409] |
| GSM7405581 |
HN-6, H3K4me3, rep1, CS029689 [VS410] |
| GSM7405582 |
HN-6, H3K4me3, rep2, CS029689 [VS411] |
| GSM7405583 |
HN-6, H3K4me3, rep3, CS029689 [VS412] |
| GSM7405584 |
5-3, H3K4me3, rep1, CS029689 [VS413] |
| GSM7405585 |
5-3, H3K4me3, rep2, CS029689 [VS414] |
| GSM7405586 |
5-3, H3K4me3, rep3, CS029689 [VS415] |
| GSM7405587 |
HN-6, negative control, rep1 [VS669] |
| GSM7405588 |
HN-6, SMYD3, rep1, CS031308 [VS671] |
| GSM7405589 |
HN-6, SMYD3, rep2, CS031308 [VS672] |
| GSM7405590 |
HN-6, SMYD3, rep3, CS031308 [VS673] |
| GSM7405591 |
5-3, SMYD3, rep1, CS031308 [VS674] |
| GSM7405592 |
HN-6, negative control, rep1 [VS531] |
| GSM7405593 |
HN6, siNC, H4K20me3, rep1, CS030666 [VS539] |
| GSM7405594 |
HN6, siNC, H4K20me3, rep2, CS030666 [VS540] |
| GSM7405595 |
HN6, siNC, H4K20me3, rep3, CS030666 [VS541] |
| GSM7405596 |
HN-6, siSMYD3, H4K20me3, rep1, CS030666 [VS542] |
| GSM7405597 |
HN-6, siSMYD3, H4K20me3, rep2, CS030666 [VS543] |
| GSM7405598 |
HN-6, siSMYD3, H4K20me3, rep3, CS030666 [VS544] |
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| This SubSeries is part of SuperSeries: |
| GSE233495 |
Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck. |
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| Relations |
| BioProject |
PRJNA975162 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE233168_RAW.tar |
4.5 Gb |
(http)(custom) |
TAR (of BED, BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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