Abstract
Lung cancer is the leading cause of death from malignant diseases worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases. NSCLC is characterized by frequent genomic imbalances and copy number variations (CNVs), but the epigenetic aberrations that are associated with clinical prognosis and therapeutic failure remain not completely identify. In the present study, a total of 55 lung cancer patients were included and we conducted genomic and genetic expression analyses, immunohistochemical protein detection, DNA methylation and chromatin immunoprecipitation assays to obtain genetic and epigenetic profiles associated to prognosis and chemoresponse of NSCLC patients. Finally, siRNA transfection-mediated genetic silencing and cisplatinum cellular cytotoxicity assays in NSCLC cell lines A-427 and INER-37 were assessed to describe chemoresistance mechanisms involved. Our results identified high frequencies of CNVs (66–51% of cases) in the 7p22.3–p21.1 and 7p15.3–p15.2 cytogenetic regions. However, overexpression of genes, such as MEOX2, HDAC9, TWIST1 and AhR, at 7p21.2–p21.1 locus occurred despite the absence of CNVs and little changes in DNA methylation. In contrast, the promoter sequences of MEOX2 and TWIST1 displayed significantly lower/decrease in the repressive histone mark H3K27me3 and increased in the active histone mark H3K4me3 levels. Finally these results correlate with poor survival in NSCLC patients and cellular chemoresistance to oncologic drugs in NSCLC cell lines in a MEOX2 and TWIST1 overexpression dependent-manner. In conclusion, we report for the first time that MEOX2 participates in chemoresistance irrespective of high CNV, but it is significantly dependent upon H3K27me3 enrichment probably associated with aggressiveness and chemotherapy failure in NSCLC patients, however additional clinical studies must be performed to confirm our findings as new probable clinical markers in NSCLC patients.
Highlights
Lung cancer remains the leading cause of cancer-related death in both the USA [1] and worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases in smokers and non-tobacco-related patients [2]
Based on the results outlined above, we propose that MEOX2 and TWIST1 overexpression is associated with reduced H3K27me3 levels and that increased H3K4me3 levels at both the MEOX2 and TWIST1 promoters participate in resistance to oncologic drugs, as likely occurred in cisplatinum/carboplatinumtreated NSCLC patients (Table 1)
As we demonstrated in the present study, high frequencies of copy number variations (CNVs), histone H3K27 and H3K4 imbalances at the 7p21 locus occur during the advanced clinical stages in NSCLC patients and NSCLC cell lines (Caucasian and Mexican Mestizo), and these features likely exist in lung precursor lesions and contribute to lung cancer progression, further studies must be conducted to confirm these hypotheses
Summary
Lung cancer remains the leading cause of cancer-related death in both the USA [1] and worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases in smokers and non-tobacco-related patients [2]. International consortiums for the study of lung cancer have used high-density SNP arrays (250 K) to describe CNVs, such as 5p15.33, 7p11.2, 14q13.3 and 17q12, as well as microdeletions at 5q11.2, 7q11.22 and 9p23 [10]. Some of these CNVs, such as gains at 14q13.3 containing the NKX2-8 [11] and NKX2-1 genes [10], have been shown to be functionally involved in growth, survival and tumorigenic activity in NSCLC [10], [11]. A genetic signature of mRNA overexpression from 7q11.23, 14q23.2 and 17q21.2 (STX1A, HIF1A and CCR7, respectively) has been identified as a predictive progression-prognosis signature during the early clinical stages of NSCLC patients [13]
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