iScience (May 2021)

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

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

Journal volume & issue
Vol. 24, no. 5
p. 102473

Abstract

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Summary: 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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