Coordinated Activation of Candidate Proto-Oncogenes and Cancer Testes Antigens via Promoter Demethylation in Head and Neck Cancer and Lung Cancer

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(3):e4961. DOI: 10.1371/journal.pone.0004961
Source: PubMed


Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported. We used an integrative method to analyze expression in primary head and neck squamous cell carcinoma (HNSCC) and pharmacologically demethylated cell lines to identify aberrantly demethylated and expressed candidate proto-oncogenes and cancer testes antigens in HNSCC.
We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS. Aberrant BORIS expression correlated with upregulation of candidate proto-oncogenes in multiple human malignancies including primary non-small cell lung cancers and HNSCC, induced coordinated proto-oncogene specific promoter demethylation and expression in non-tumorigenic cells, and transformed NIH3T3 cells.
Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.

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    • "These increased levels of BORIS correlated with the tumour size and grade in these tumour entities (Martin-Kleiner, 2012). Experiments in cell lines have suggested that BORIS expression is sufficient to simultaneously demethylate and activate the transcription of CTAs and oncogenes, such as Myc (Hong et al, 2005; Vatolin et al, 2005; Nguyen et al, 2008; Smith et al, 2009), and may induce the expression of MAGE-A1 (Vatolin et al, 2005). BORIS is considered to be a new oncogene, because it may inhibit apoptosis in cancer cells by activating transcription of hTERT essential for telomerase activity (Renaud et al, 2011). "
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    ABSTRACT: Background: MAGE-A (melanoma-associated antigen-A) are promising targets for specific immunotherapy and their expression may be induced by the epigenetic factor BORIS. Methods: To determine their relevance for breast cancer, we quantified the levels of MAGE-A1, -A2, -A3, -A12 and BORIS mRNA, as well as microRNAs let-7b and miR-202 in pre- and postoperative serum of 102 and 34 breast cancer patients, respectively, and in serum of 26 patients with benign breast diseases and 37 healthy women by real-time PCR. The mean follow-up time of the cancer patients was 6.2 years. Results: The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001). In uni- and multivariate analyses, high levels of miR-202 significantly correlated with poor overall survival (P=0.0001). Transfection of breast cancer cells with synthetic microRNAs and their inhibitors showed that let-7b and miR-202 did not affect the protein expression of MAGE-A1. Conclusions: Based on their cancer-specific increase in breast cancer patients, circulating MAGE-A and BORIS mRNAs may be further explored for early detection of breast cancer and monitoring of MAGE-directed immunotherapies. Moreover, serum miR-202 is associated with prognosis.
    British Journal of Cancer 07/2014; 111(5). DOI:10.1038/bjc.2014.360 · 4.84 Impact Factor
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    • "Consistent with this hypothesis, other studies have shown that inhibiting DNA methyltransferase (DNMT) activity with 5 aza-deoxycytidine (5 AZA) results in robust somatic expression of a set of CTAs both in vitro and in vivo[31]. However, only a few studies have experimentally confirmed promoter demethylation following DNMT inhibition by 5AZA or silencing by siRNA [13,32] and in many cases CTA genes that lack CpG dinucleotides respond to DNMT inhibition while in other cases, despite the presence of CpG dinucleotides, the CTA genes are not derepressed. For instance, the SPANX genes, which lack a CpG island in the promoter region [33], respond robustly to 5 AZA treatments [34] implicating an indirect mechanisms underlying the response, although the presence of such sites at distal regions or within introns cannot be ruled out. "
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    ABSTRACT: Background The Cancer/Testis Antigens (CTAs) are a heterogeneous group of proteins whose expression is typically restricted to the testis. However, they are aberrantly expressed in most cancers that have been examined to date. Broadly speaking, the CTAs can be divided into two groups: the CTX antigens that are encoded by the X-linked genes and the non-X CT antigens that are encoded by the autosomes. Unlike the non-X CTAs, the CTX antigens form clusters of closely related gene families and their expression is frequently associated with advanced disease with poorer prognosis. Regardless however, the mechanism(s) underlying their selective derepression and stage-specific expression in cancer remain poorly understood, although promoter DNA demethylation is believed to be the major driver. Methods Here, we report a systematic analysis of DNA methylation profiling data from various tissue types to elucidate the mechanism underlying the derepression of the CTAs in cancer. We analyzed the methylation profiles of 501 samples including sperm, several cancer types, and their corresponding normal somatic tissue types. Results We found strong evidence for specific DNA hypomethylation of CTA promoters in the testis and cancer cells but not in their normal somatic counterparts. We also found that hypomethylation was clustered on the genome into domains that coincided with nuclear lamina-associated domains (LADs) and that these regions appeared to be insulated by CTCF sites. Interestingly, we did not observe any significant differences in the hypomethylation pattern between the CTAs without CpG islands and the CTAs with CpG islands in the proximal promoter. Conclusion Our results corroborate that widespread DNA hypomethylation appears to be the driver in the derepression of CTA expression in cancer and furthermore, demonstrate that these hypomethylated domains are associated with the nuclear lamina-associated domains (LADS). Taken together, our results suggest that wide-spread methylation changes in cancer are linked to derepression of germ-line-specific genes that is orchestrated by the three dimensional organization of the cancer genome.
    BMC Cancer 03/2013; 13(1):144. DOI:10.1186/1471-2407-13-144 · 3.36 Impact Factor
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    • "Reported changes involve genome-wide hypomethylation as well as gene-specific hypermethylation,11 both of which are associated with cancer.28 Hypomethylation can result in oncogenes that should be suppressed, becoming expressed (e.g., as in loss of imprinting).29 Hypermethylation on the other hand, can silence tumor suppressor genes that defend against cancer.30 "
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    ABSTRACT: The current approach to treatment in oncology is to replace the generally cytotoxic chemotherapies with pharmaceutical treatment which inactivates specific molecular targets associated with cancer development and progression. The goal is to limit cellular damage to pathways perceived to be directly responsible for the malignancy. Its underlying assumptions are twofold: (1) that individual pathways are the cause of malignancy; and (2) that the treatment objective should be destruction-either of the tumor or the dysfunctional pathway. However, the extent to which data actually support these assumptions has not been directly addressed. Accumulating evidence suggests that systemic dysfunction precedes the disruption of specific genetic/molecular pathways in most adult cancers and that targeted treatments such as kinase inhibitors may successfully treat one pathway while generating unintended changes to other, non-targeted pathways. This article discusses (1) the systemic basis of malignancy; (2) better profiling of pre-cancerous biomarkers associated with elevated risk so that preventive lifestyle modifications can be instituted early to revert high-risk epigenetic changes before tumors develop; (3) a treatment emphasis in early stage tumors that would target the restoration of systemic balance by strengthening the body's innate defense mechanisms; and (4) establishing better quantitative models of systems to capture adequate complexity for predictability at all stages of tumor progression.
    Gene regulation and systems biology 02/2013; 7(1):11-22. DOI:10.4137/GRSB.S10943
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