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Published on: August 23, 2019
Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth
Haroula Kontaki1, Marina Koukaki1, Maria Vasilarou1,2
1Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece.
Abstract:
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 hepatocellular carcinoma (HCC). Here, we show that targeting Smyd3 by next-generation antisense oligonucleotides (Smyd3-ASO) is an efficient approach to modulate its mRNA levels in vivo and to halt the growth of already initiated liver tumors. Smyd3-ASO treatment dramatically decreased tumor burden in a mouse model of chemically induced HCC and negatively affected the growth rates, migration, oncosphere formation, and xenograft growth capacity of a panel of human hepatic cancer cell lines. Smyd3-ASOs prevented the activation of oncofetal genes and the development of cancer-specific gene expression program. The results point to a mechanism by which Smyd3-ASO treatment blocks cellular de-differentiation, a hallmark feature of HCC development, and, as a result, it inhibits the expansion of hepatic cancer stem cells, a population that has been presumed to resist chemotherapy.
Insights
Targeting Smyd3 with antisense oligonucleotides (Smyd3-ASO) effectively halts liver tumor growth in mice and human cancer cells. Smyd3-ASO treatment inhibits cancer stem cell expansion and de-differentiation in hepatocellular carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- The Smyd3 protein, a methyltransferase, promotes oncogenesis and is implicated in hepatocellular carcinoma (HCC).
- Targeting oncogenic drivers is a key strategy in cancer therapy.
Purpose of the Study:
- To investigate the efficacy of Smyd3-targeting antisense oligonucleotides (Smyd3-ASO) in inhibiting HCC growth.
- To elucidate the mechanism by which Smyd3-ASO affects cancer cell behavior and stemness.
Main Methods:
- Administration of Smyd3-ASO in a mouse model of chemically induced HCC.
- Assessment of Smyd3-ASO effects on human hepatic cancer cell lines in vitro and in xenograft models.
- Analysis of gene expression changes, including oncofetal genes and cancer-specific programs.
- Evaluation of cellular de-differentiation and cancer stem cell properties.
Main Results:
- Smyd3-ASO treatment significantly reduced tumor burden in a mouse HCC model.
- Smyd3-ASO inhibited growth rates, migration, and oncosphere formation in hepatic cancer cell lines.
- Xenograft growth capacity was diminished by Smyd3-ASO treatment.
- Smyd3-ASO prevented oncofetal gene activation and blocked cellular de-differentiation, impacting hepatic cancer stem cells.
Conclusions:
- Smyd3-ASO is a promising therapeutic strategy for hepatocellular carcinoma.
- Targeting Smyd3 with Smyd3-ASO halts HCC progression by inhibiting de-differentiation and cancer stem cell expansion.
- This approach offers potential for overcoming chemotherapy resistance in HCC.
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