Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers diagnosed worldwide and is associated with a 5-year survival rate of 55%. EZH2, a component of the polycomb repressor complex 2, trimethylates H3K27 (H3K27me3), which has been shown to drive squamous differentiation in normal keratinocytes. This study determined whether inhibition of EZH2-mediated epigenetic silencing could induce differentiation or provide therapeutic benefit in HNSCC. We determined the effects of inhibiting EZH2, by either RNA interference or pharmacologically, on HNSCC growth, viability, and differentiation in vitro. Xenografts of HNSCC cell lines were used to assess efficacy of 3-deazaneplanocin A (DZNep), an inhibitor of H3K27 trimethylation, in vivo. EZH2 was highly expressed in HNSCC cell lines in vitro and tissue microarray analysis revealed high expression in (n = 59) in situ relative to normal oral epithelium (n = 12). Inhibition of EZH2 with siRNA could induce expression of differentiation genes in differentiation-refractory squamous cell carcinoma cell lines. Differentiation-refractory HNSCC cell lines displayed persistent H3K27me3 on the promoters of differentiation genes. DZNep caused cancer-cell-specific apoptosis in addition to a profound reduction in colony-forming efficiency and induction of some squamous differentiation genes. Furthermore, in vivo, DZNep attenuated tumor growth in two different xenograft models, caused intratumor inhibition of EZH2, and induction of differentiation genes in situ. Collectively, these data suggest that aberrant differentiation in HNSCC may be attributed to epigenetic dysregulation and suggest that inhibition of PRC2-mediated gene repression may represent a potential therapeutic target.
Highlights
Squamous differentiation is a complex, tightly regulated process involving the coordinated induction and repression of genes involved in keratinocyte, proliferation, differentiation, and stem cell maintenance
EZH2 was highly expressed in Head and neck squamous cell carcinoma (HNSCC) cell lines in vitro and tissue microarray analysis revealed high expression in (n 1⁄4 59) in situ relative to normal oral epithelium (n 1⁄4 12)
In vivo, deazaneplanocin A (DZNep) attenuated tumor growth in two different xenograft models, caused intratumor inhibition of EZH2, and induction of differentiation genes in situ. Collectively, these data suggest that aberrant differentiation in HNSCC may be attributed to epigenetic dysregulation and suggest that inhibition of polycomb repressor complex 2 (PRC2)-mediated gene repression may represent a potential therapeutic target
Summary
Squamous differentiation is a complex, tightly regulated process involving the coordinated induction and repression of genes involved in keratinocyte, proliferation, differentiation, and stem cell maintenance. Maintaining a balance between the relative abundance and spatial positioning of stem cells, proliferating transit amplifying cells and the terminally growth-arrested differentiated keratinocytes in stratified squamous epithelium is primarily achieved via transcriptional activation and repression An epigenetic modification, which has attracted much interest is tri-methylation of lysine 27 on histone H3 (H3K27me3) by the polycomb repressor complex 2 (PRC2). Squamous differentiation [7, 8], adipogenesis [9], and myogenesis [10, 11] are characterized by dynamic changes in H3K27me occupation of key differentiation-associated genes. H3K27me is found to be associated with the promoters of a subset of differentiation genes in proliferating keratinocytes [12]. Demethylation of H3K27me is catalyzed by the lysine 27-specific demethylases, JMJD3 and UTX [13], with JMJD3-
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