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Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the  TOX2  promoter.  TOX2  was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel  TOX2  transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to  TOX ,  TOX3 , and  TOX4  genes that share similar genomic structure and protein homology with  TOX2  revealed distinct methylation profiles by smoking status, histology, and cancer type.  TOX  was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas  TOX3  was frequently methylated in lung (58%) than breast (30%) tumors.  TOX4  was unmethylated in all samples and showed the highest expression in normal lung. Compared to  TOX4 , expression of  TOX ,  TOX2  and  TOX3  in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated  TOX2  knockdown modulated multiple pathways while  TOX3  inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells  in vitro , the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment.

Differential Epigenetic Regulation of TOX Subfamily High Mobility Group Box Genes in Lung and Breast Cancers