Integrative Discovery of Epigenetically Derepressed Cancer Testis Antigens in NSCLC

Glazer, Chad A.; Smith, Ian; Ochs, Michael F.; Begum, Shahnaz; Westra, William H.; Chang, Steven S.; Sun, Wenyue; Bhan, Sheetal; Khan, Zubair; Ahrendt, Steven A.; Califano, Joseph A.

doi:10.1371/journal.pone.0008189

Cited by 66 publications

(80 citation statements)

References 41 publications

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“…Yet, it should be kept in mind that the impact of the epigenetic treatment can differ between tumors, and although it could benefit some patients, it might also cause adverse tumor-supportive effects in others. 47 Thus, better criteria for stratifying candidates for epigenetic therapy are strongly needed.…”

Section: Discussionmentioning

confidence: 99%

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

et al. 2015

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MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumorsuppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

et al. 2015

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“…[24][25][26][27] Abnormal gene expression in tumor cells may result from alterations in copy number, sequence mutations, and/or epigenetic dysregulation. Malignant cancer cells have been shown to exhibit major disruptions in their DNA methylation profiles, and these changes have also been shown to include aberrant hypermethylation or hypomethylation of gene CpG islands.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Shin

Jin

Hwang

et al. 2015

Laboratory Investigation

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Muscarinic receptors, particularly the type 3 subtype (M3R), have an important role in exocrine secretion. M3R normally function in HSG cells originated from human submandibular gland ducts, but not in A253 and SGT cells, derived from human submandibular carcinoma and salivary gland adenocarcinoma. However, the underlying mechanism of this suppression has remained elusive. In this study, we examined whether M3R function is suppressed by epigenetic modulation of the receptor. To this end, we investigated the mRNA transcript and protein levels of the M3R using reverse transcriptase-PCR, western blot, and confocal microscopy analyses. Global DNA methylation assays, methylation-specific PCR, and bisulfite sequencing were also performed to understand the epigenetic status of the M3R CpG island. We found that A253 cells expressed all subtypes of muscarinic receptors, except M3R, on the mRNA level. However, treatment of cells with 5-aza-2 0 -deoxycytidine (5-Aza-CdR), a DNA-demethylating agent, increased the expression levels of both M3R mRNA transcript and protein in proportion to the incubation period. 5-Aza-CdR completely restored the carbacholinduced calcium response, which was not observed in untreated A253 cells. In untreated A253 cells, all CG pairs from the 1st to 14th were methylated and 5-Aza-CdR treatment demethylated one of the methylated CG pairs. We also examined the methylation pattern of M3R CpG island in human cancer tissue. Interestingly, the result was very similar to those of A253 cells. All CG pairs in M3R CpG island were also methylated. Another salivary gland tumor cell line, SGT, also showed the similar methylation pattern, heavy methylation in M3R CpG island. It is concluded that CpG island in M3R is hypermethylated in cancer cell lines and human cancer. Our results further suggest that 5-Aza-CdR could potentially be used to restore the function of M3R, suppressed in some cancer cell types. Epigenetic regulation by CpG methylation has an important role in tumorigenesis, and is also crucial to mounting a successful response to cancer therapy. CpG islands in DNA are methylated de novo in a tissue-specific manner, and the patterns of methylation are fixed in subsequent cell divisions by methyltransferase activity. 1 Recent studies have indicated that hypermethylation of CpG islands within the promoter and 5 0 regions of genes is an important epigenetic mechanism for suppressing gene expression. 2-4 DNA hypermethylation may directly affect the basal transcriptional machinery by altering the secondary structure of DNA and inducing chromosome remodeling through methyl group-binding proteins and histone deacetylase, thereby leading to transcriptional repression. 5 5-Aza-2 0 -deoxycytidine (5-Aza-CdR, decitabine) is a prodrug that has been shown to be phosphorylated, and thus activated, by deoxytidine kinase. 5-Aza-CdR is a nucleotide analog that is incorporated into DNA, where it irreversibly inactivates DNA methyltransferase (DNMT); 5-Aza-CdR is also an S-phase-specific agent. 6 The cytosine DNMT gen...

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“…Gene expression was considered to be associated with methylation if the Spearman correlation coefficient was less than -0.4, demonstrating inverse correlation between methylation status and gene expression. To analyze the effect of DNA methylation in nonmalignant lung cell lines, we used publically available gene expression data sets in which the human bronchial epithelial cells and human small airway epithelial cells were treated with AZA (GSE18454) (65). Mean β values of each probe were calculated in both tumor and normal lungs, and Δβ values (normal -tumor) > 0.1 were defined as hypomethylated.…”

Section: Methodsmentioning

confidence: 99%

Profiling cancer testis antigens in non–small-cell lung cancer

Djureinovic¹,

Hallström²,

Horie³

et al. 2016

JCI Insight

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Integrative Discovery of Epigenetically Derepressed Cancer Testis Antigens in NSCLC

Cited by 66 publications

References 41 publications

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Profiling cancer testis antigens in non–small-cell lung cancer

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