Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression
Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Animals; Cell Line, Tumor; Cell Proliferation; DNA (Cytosine-5-)-Methyltransferase; Down-Regulation; Gene Expression Regulation, Neoplastic; *Gene Silencing; Genome, Human; Homeodomain Proteins; Humans; Lung Neoplasms; Mice; Promoter Regions, Genetic; Protein Binding; RNA, Small Interfering; Repressor Proteins; Tumor Suppressor Proteins
Genetics and Genomics
The RASSF1A tumor suppressor gene is epigenetically silenced in a variety of cancers. Here, we perform a genome-wide human shRNA screen and find that epigenetic silencing of RASSF1A requires the homeobox protein HOXB3. We show that HOXB3 binds to the DNA methyltransferase DNMT3B gene and increases its expression. DNMT3B, in turn, is recruited to the RASSF1A promoter, resulting in hypermethylation and silencing of RASSF1A expression. DNMT3B recruitment is facilitated through interactions with Polycomb repressor complex 2 and MYC, which is bound to the RASSF1A promoter. Mouse xenograft experiments indicate that the oncogenic activity of HOXB3 is due, at least in part, to epigenetic silencing of RASSF1A. Expression analysis in human lung adenocarcinoma samples reveals that RASSF1A silencing strongly correlates with overexpression of HOXB3 and DNMT3B. Analysis of human cancer cell lines indicates that the RASSF1A epigenetic silencing mechanism described here may be common in diverse cancer types.
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Citation: Mol Cell. 2009 Oct 23;36(2):219-30. Link to article on publisher's site