Journal
ISCIENCE
Volume 24, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.102473
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Funding
- AXA Research Fund Epigenetics Chair Program
- Hellenic Foundation for Research and Innovation [1996]
- ERDF, Research-Create-Innovate grant [T1EDK-00407]
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Research has shown that targeting Smyd3 with Smyd3-ASO is an efficient approach to reduce tumor burden in a mouse model of HCC, halt the growth of liver tumors, and slow down the growth rates, migration, and xenograft growth capacity of human hepatic cancer cell lines. Smyd3-ASOs also prevent the activation of oncogenic genes and the development of cancer-specific gene expression program, ultimately inhibiting the expansion of hepatic cancer stem cells.
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.
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