Epigenetic Modulation of EGFR-Signaling Genes in HNSCC
Lindsey N Clark, Haihong Zhang, Steve A Schichman, Chunyang Fan. Univ Arkansas for Med Sciences, Little Rock, AR; Central Arkansas Veterans Healthcare System, Little Rock, AR
Background: Epidermal Growth Factor Receptor (EGFR) signaling pathway appears critically important in the pathogenesis of head and neck squamous cell carcinomas (HNSCC). For the above reason, there has been immense interest in exploring targeted therapies aiming at EGFR, using either EGFR tyrosine kinase inhibitors (EGFR-TKI) or anti-EGFR monoclonal antibodies (EGFR-mab) for HNSCC. Characterization of epigenetic regulation of EGFR signaling genes (EGFR, E-Cadherin, PTEN and SCOS1) may lead to more effective treatment of HNSCC using EGFR-targeted therapies.
Design: Promoter sequences of 4 EGFR signaling genes (EGFR, E-cadherin, PTEN and SCOS1) were analyzed for the presence or absence of CPG island using CpG Plot software. Total RNA samples were extracted, followed by real-time RNA analyses for these 4 genes from 8 cultured HNSCC cell lines, treated with or without a DNA demethylating agent, 5-aza-cytidine.
Results: All 4 EGFR signaling genes (EGFR, E-cadherin, PTEN and SCOS1) contain a CpG island in their respective promoter sequence, ranging from 233 to 602 basepairs. Following treatment with a DNA methylation inhibitor, 5-azacytidine, increased expression of EGFR, E-cadherin, PTEN and SCOS1 genes was seen in 4/8 (50%), 4/8 (50%), 1/8 (12%) and 5/8 (62%) HNSCC lines respectively as compared to their original cells without 5-aza cytidine treatment.
Conclusions: The presence of a CpG island in the promoter region and increased gene expression in response to DNA demethylation support that the expression of 3 EGFR signaling genes (EGFR, E-cadherin, SCOS1) may be suppressed by promoter hypermethylation and these genes can be unregulated by DNA demethylating agent in HNSCC. Therefore, DNA demethylating agent may be used to improve the response rate for HNSCC treated with EGFR-targeted agents (EGFR-TKI or (EGFR-mab).
Category: Head & Neck
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 186, Wednesday Morning