A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness
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David Cheishvili1,*, Barbara Stefanska1,6,*, Cao Yi1, Chen Chen Li1, Patricia Yu1, Ani Arakelian2, Imrana Tanvir3, Haseeb Ahmed Khan3, Shafaat Rabbani2, Moshe Szyf1,4,5,*
1Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
2Departments of Medicine, Oncology, and Pharmacology, McGill University, Montreal, Quebec, Canada
3Department of Pathology, Fatima Memorial Hospital System Lahore, Pakistan
4Department of Pharmacology and Therapeutics, Sackler Program for Epigenetics & Developmental Psychobiology, McGill University Medical School, Montreal, Quebec, Canada
5Department of Pharmacology and Therapeutics, Canadian Institute for Advanced Research, Montreal, Quebec, Canada
6Department of Nutrition Science, Purdue University, West Lafayette, USA
*These authors have contributed equally to this work
Moshe Szyf, e-mail: [email protected]
Keywords: DNA methylation, epigenetics, inasiveness, drug targets, hypomethylation
Received: July 29, 2015 Accepted: September 10, 2015 Published: September 22, 2015
Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from non-invasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes in cellular invasiveness from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness.
SUMMARY: Our study provides evidence that common DNA hypomethylation signature exists between cancer cells derived from different tissues, pointing to a common mechanism of cancer invasiveness in cancer cells from different origins that could serve as drug targets.
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