Journal
EPIGENETICS
Volume 10, Issue 6, Pages 545-561Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15592294.2015.1048953
Keywords
HNSCC, Head and neck squamous cell cancer; IGFBP3, Insulin-like growth factor-binding protein 3; RXR, Retinoid X receptor; AraC, Cytosine arabinoside; SOCS3, Suppressor of cytokine signaling 3; EIF2AK2, Eukaryotic translation initiation factor 2-alpha kinase 2; ILK, Integrin linked kinase; CDK4, Cyclin-dependent kinase 4; dmCpG, differentially methylated CpG; CDKN1A, Cyclin-dependent kinase inhibitor 1A (p21, Cip1); PCNA, Proliferating cell nuclear antigen; LXR, Liver X receptor; FASN, Fatty acid synthase; IPA, Ingenuity pathway analysis; GSK-3, Glycogen synthase kinase 3; HM450, HumanMethylation450; NFATC2, Nuclear factor of activated t-cells cytoplasmic 2; CCNA1, Cyclin A1; 5-Aza, 5-aza-2 ' deoxycitidine; PTEN, Phosphatase and tensin homolog; IRF1, Interferon regulatory factor 1; MGMT, O6-methylguanine DNA methyltransferase; CCND2, Cyclin D2; SAM, S-Adenosylmethionine; hTERT, human telomerase reverse transcriptase; DNMT, DNA methyltransferase; AKT, Protein kinase B; STAT1, Signal transducers and activators of transcription 1; KLF4, Kruppel-like factor 4; KRT19, Keratin 19, LIPG, Endothelial lipase; VHL, Von Hippel-Lindau tumor suppressor; TCGA, The Cancer Genome Atlas; Head and neck squamous cell cancer (HNSCC); The Cancer Genome Atlas (TCGA); Gene expression; DNA methylation; Radiation resistance
Funding
- National Cancer Institute of the National Institutes of Health [R01 CA136810, R01LM010185]
- Wake Forest School of Medicine
- Wake Forest University Structural and Computational Biophysics training program [T32 GM095440]
- Comprehensive Cancer Center of Wake Forest University NCI CCSG [P30CA012197]
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Resistance to radiation therapy constitutes a significant challenge in the treatment of head and neck squamous cell cancer (HNSCC). Alteration in DNA methylation is thought to play a role in this resistance. Here, we analyzed DNA methylation changes in a matched model of radiation resistance for HNSCC using the Illumina HumanMethylation450 BeadChip. Our results show that compared to radiation-sensitive cells (SCC-61), radiation-resistant cells (rSCC-61) had a significant increase in DNA methylation. After combining these results with microarray gene expression data, we identified 84 differentially methylated and expressed genes between these 2 cell lines. Ingenuity Pathway Analysis revealed ILK signaling, glucocorticoid receptor signaling, fatty acid alpha-oxidation, and cell cycle regulation as top canonical pathways associated with radiation resistance. Validation studies focused on CCND2, a protein involved in cell cycle regulation, which was identified as hypermethylated in the promoter region and downregulated in rSCC-61 relative to SCC-61 cells. Treatment of rSCC-61 and SCC-61 with the DNA hypomethylating agent 5-aza-2'deoxycitidine increased CCND2 levels only in rSCC-61 cells, while treatment with the control reagent cytosine arabinoside did not influence the expression of this gene. Further analysis of HNSCC data from The Cancer Genome Atlas found increased methylation in radiation-resistant tumors, consistent with the cell culture data. Our findings point to global DNA methylation status as a biomarker of radiation resistance in HNSCC, and suggest a need for targeted manipulation of DNA methylation to increase radiation response in HNSCC.
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