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

Autor:	Kontaki H; Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece., Koukaki M; Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece., Vasilarou M; Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece.; Department of Biology, University of Crete, 70013 Herakleion, Crete, Greece., Giakountis A; Department of Biochemistry and Biotechnology, University of Thessaly, Larissa 41500, Greece., Deligianni E; Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece., Luo X; Ionis Pharmaceuticals, Carlsbad, CA, USA., Kim Y; Ionis Pharmaceuticals, Carlsbad, CA, USA., Talianidis I; Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 Apr 24; Vol. 24 (5), pp. 102473. Date of Electronic Publication: 2021 Apr 24 (Print Publication: 2021).
DOI:	10.1016/j.isci.2021.102473
Abstrakt:	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. Competing Interests: Y.K. and X.L. are employees and shareholders of Ionis Pharmaceuticals. All other authors declare no potential conflicts of interest. (© 2021 The Authors.)
Databáze:	MEDLINE
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