Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth

Kontaki, Haroula; Koukaki, Marina; Vasilarou, Maria; Giakountis, Antonis; Deligianni, Elena; Luo, Xiaolin; Kim, Youngsoo; Talianidis, Iannis

doi:10.1016/j.isci.2021.102473

Cited by 11 publications

(13 citation statements)

References 47 publications

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“…The link between the gene expression signature of embryonic and cancerous cells and tissues has been demonstrated by many previous studies [143][144][145][146]. Many postnatally silenced hepatic genes are reactivated in hepatocellular carcinoma and are called "oncofetal" genes to reflect the context of their expression [147][148][149]. In agreement with these studies, it was found that a group of oncofetal genes is bound by C/EBPα or HNF4α during embryogenesis.…”

Section: Significance Of Bookmarking In Cancer and Proliferation-induced Genessupporting

confidence: 63%

Transcription Control of Liver Development

Tachmatzidi

Galanopoulou

Talianidis

2021

Cells

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During liver organogenesis, cellular transcriptional profiles are constantly reshaped by the action of hepatic transcriptional regulators, including FoxA1-3, GATA4/6, HNF1α/β, HNF4α, HNF6, OC-2, C/EBPα/β, Hex, and Prox1. These factors are crucial for the activation of hepatic genes that, in the context of compact chromatin, cannot access their targets. The initial opening of highly condensed chromatin is executed by a special class of transcription factors known as pioneer factors. They bind and destabilize highly condensed chromatin and facilitate access to other “non-pioneer” factors. The association of target genes with pioneer and non-pioneer transcription factors takes place long before gene activation. In this way, the underlying gene regulatory regions are marked for future activation. The process is called “bookmarking”, which confers transcriptional competence on target genes. Developmental bookmarking is accompanied by a dynamic maturation process, which prepares the genomic loci for stable and efficient transcription. Stable hepatic expression profiles are maintained during development and adulthood by the constant availability of the main regulators. This is achieved by a self-sustaining regulatory network that is established by complex cross-regulatory interactions between the major regulators. This network gradually grows during liver development and provides an epigenetic memory mechanism for safeguarding the optimal expression of the regulators.

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Section: Significance Of Bookmarking In Cancer and Proliferation-induced Genessupporting

confidence: 63%

Transcription Control of Liver Development

Tachmatzidi

Galanopoulou

Talianidis

2021

Cells

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“…Evaluation of the expression levels of immune-related genes revealed upregulation of multiple key type I IFN response genes, such as MX1 , MX2 , CD274 , IL1B , GBP2 , IL6 ( IFN-β ), and APM genes, such as TAP2 , TAPBP , B2M , and HLA-A and -B ( Fig.1A , Supplementary Fig.1A, B ). This phenotype was reproduced with pharmacological targeting of SMYD3 using SMYD3 ASOs (Kontaki et al, 2021, Ionis Pharmaceuticals) ( Fig.1B , Supplementary Fig.2A, B) . Consistently, the RNA-seq profile of a SMYD3 CRISPR knockout (KO) cell line (termed 5-3) was compared with those of parental HN-6 cells, and exhibited a similar phenotype ( Fig.1C , Supplementary Fig.3 A, B) .…”

Section: Resultsmentioning

confidence: 89%

“…SMYD3 inhibitors are actively in development (Peserico et al, 2015, Mitchell et al, 2015, Huang et al, 2019, augmenting siRNA and CRISPR as tools for investigation of the mechanism and therapeutic potential of SMYD3. Recently, Kontaki et al (Kontaki et al, 2021) showed that next generation anti-sense oligonucleotides (ASOs) targeting Smyd3 decreased Smyd3 mRNA levels in vivo efficiently and halted the growth of liver tumors in a chemically induced HCC mouse model.…”

Section: Introductionmentioning

confidence: 99%

“…SMYD3 inhibitors are actively in development (Peserico et al, 2015, Mitchell et al, 2015, Huang et al, 2019), augmenting siRNA and CRISPR as tools for investigation of the mechanism and therapeutic potential of SMYD3. Recently, Kontaki et al (Kontaki et al, 2021) showed that next generation anti-sense oligonucleotides (ASOs) targeting Smyd3 decreased Smyd3 mRNA levels in vivo efficiently and halted the growth of liver tumors in a chemically induced HCC mouse model. ASOs are a promising drug discovery platform of RNA-targeted therapeutics involving single-stranded, chemically modified DNA oligonucleotides, and constitute an alternative drug platform over enzymatic inhibitors or antibodies (Crooke et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

Nigam

Bernard

Kim

et al. 2022

Preprint

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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 prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss 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 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 and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the 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 was associated with poor response to 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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“…The oncogenic function of suppressor of variegation, enhancer of zeste, and Myeloid-Nervy-DEAF1-domain family methyltransferase Smyd3 has been implicated in various malignancies, including HCC. Treatment with Smyd3-ASO blocks the cell dedifferentiation process and reduces the burden of DENinduced liver cancer (Kontaki et al, 2021).…”

Section: Application Of Antisense Oligonucleotide In Liver Cancermentioning

confidence: 99%

Antisense oligonucleotide is a promising intervention for liver diseases

Fan

Zou

2022

Front. Pharmacol.

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As the body’s critical metabolic organ, the liver plays an essential role in maintaining proper body homeostasis. However, as people’s living standards have improved and the number of unhealthy lifestyles has increased, the liver has become overburdened. These have made liver disease one of the leading causes of death worldwide. Under the influence of adverse factors, liver disease progresses from simple steatosis to hepatitis, to liver fibrosis, and finally to cirrhosis and cancer, followed by increased mortality. Until now, there has been a lack of accepted effective treatments for liver disease. Based on current research, antisense oligonucleotide (ASO), as an alternative intervention for liver diseases, is expected to be an effective treatment due to its high efficiency, low toxicity, low dosage, strong specificity, and additional positive characteristics. In this review, we will first introduce the design, modification, delivery, and the mechanisms of ASO, and then summarize the application of ASO in liver disease treatment, including in non-alcoholic fatty liver disease (NAFLD), hepatitis, liver fibrosis, and liver cancer. Finally, we discuss challenges and perspectives on the transfer of ASO drugs into clinical use. This review provides a current and comprehensive understanding of the integrative and systematic functions of ASO for its use in liver disease.

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Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth

Cited by 11 publications

References 47 publications

Transcription Control of Liver Development

Transcription Control of Liver Development

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

Antisense oligonucleotide is a promising intervention for liver diseases

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