Abstract
In most cases, cancer develops as a result of non-inheritable somatic mutations (epimutations), acquired by the individual adult cell, during the evolution of the cell, and propagated into an expanding clone of progeny of the cells by natural selection [1]. The role of microenvironment in selection for such acquired mutations, or epimutations, is a focus of scientific research in carcinogenesis [2]. Here we describe a defective DNA response to hypoxia due to epigenetic aberrancies, in cancer cellular biology [3]. We also summarize a literature review on hypoxia mediated epigenetic responses, and its role in carcinogenesis and metastasis. Further, we review a novel method of treating hypoxic solid tumors with a combination of epigenetic modifiers with both in vitro and in vivo results in human, translating to an improved prognosis and clinical outcome. We propose that this approach both independently and synergistically (with the current standard of care) can provide an improved outcome.
Highlights
Given its central role in tumor progression and resistance to therapy, tumor hypoxia might well be considered the best validated target that has yet to be exploited in oncology [1] [4]-[20]
These series of enzymes are mutated in the event of exposure to carcinogens and inactivating mutations in such enzymes controlling histone modification have been detected in variety of solid tumors including clear cell renal carcinoma, clear cell ovarian cancer, and pancreatic neuroendocrine tumors [41] [42]
His PSA as well dropped down to 14 measured on 5/29/15. ► His circulatory tumor cells were analyzed and it showed positive C MYC on 5/6/15 and it was repeated on 5/21/15 and it was negative. (No presence of CTC in blood). ► This is an important result as it indicates that ► C MYC positive CTC respond to this protocol, and through this case we showed that C MYC may for the first time be considered an actionable target. ► The patient continues the treatment at our clinic, with excellent results. (Complete radiological remission)
Summary
Given its central role in tumor progression and resistance to therapy, tumor hypoxia might well be considered the best validated target that has yet to be exploited in oncology [1] [4]-[20]. A hypoxia-induced epigenetic silencing of the tumor suppressor RUNX3 through histone H3-lysine 9 dimethylation and decreased H3 acetylation during disease progression has been observed, which is reversible by administration of cytosine-methylation inhibitor 5-aza-2-deoxycytidine and Trichostatin A [43] This demonstrated that the concept of combination therapy with both HDACI and DNMTI could reverse the histone methyltransferase and HDAC1 up-regulation following hypoxia (increase in the repressive histone mark H3K9me and a decrease in the transcriptionally active H3K9 acetylation marks) [40] [44]. The class III HDAC inhibitor SirtI has been found to deacetylate HIF-1α and HIF-2α, repressing HIF activity [46] [47]
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