摘要：SummaryThe 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 levelsin vivoand 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.Graphical abstractDisplay OmittedHighlights•New generation antisense oligonucleotides efficiently silence Smyd3in vivo.•Smyd3-ASO treatment inhibits the growth of already initiated liver tumors.•Smyd3-ASO treatment prevents the activation of oncofetal and CSC-specific genes.•Smyd3-ASO-sensitive gene signature specifies a de-differentiated phenotype.Cancer; Epigenetics
