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Epigenetic Reprogramming, Quiescence, and the Cancer Burden

" The time has come," the Walrus said, "To talk of many things: Of shoes-and ships-and sealing-wax- Of cabbages-and kings- And why the sea is boiling hot- And whether pigs have wings.", (The Walrus and the Carpenter from Through the Looking Glass-Lewis Carroll)

The time has come to talk of many things. Of cancer, nurture, and genes that are sound but not sound. Of epigenomics and methylones. Of FoxOs, mTOR, and HIFs. Of cancer stem cells, quiescence, and pluripotency. Of pocket handkerchiefs, sobs, tears, and lost hope. Of epigenetic reprogramming, pigs that fly, and the renewal of lost hope.

The time has come to talk of many things. Of cancer, nurture, and genes that are sound but not sound. Of epigenomics and methylones. Of FoxOs, mTOR, and HIFs. Of cancer stem cells, quiescence, and pluripotency. Of pocket handkerchiefs, sobs, tears, and lost hope. Of epigenetic reprogramming, pigs that fly, and the renewal of lost hope. First though epigenetic reprogramming.

Epigenetic reprogramming is a phenomenon-or epiphenomenon (depending on your looking glass) - that generates mitotically heritable changes that do not involve alterations to the DNA sequence. DNA methylation, histone modifications, and chromatin reorganization are the main epigenetic mechanisms associated with cancer. Methylation of DNA is mediated by DNA methyltransferases (DNMTs) which are enzymes that add methyl groups to cytosines in both RNA and DNA molecules. DNA methylation causes cancer by inhibiting transcription following the formation of a complex comprising of methyl groups and other proteins hence preventing transcription factors from accessing the gene promoters. It is also opined that DNA methylation is a result rather than a cause of gene inactivation and occurs when mutations expose the promoter regions, rendering them more prone to the action of DNMTs. Global hypomethylation of genes such as MYC and H-ras leads to chromosomal instability and is often an early event in tumorigenesis. Hypermethylation of CpG islands and promoter regions is also observed in cancer. Examples of genes that are hypermethylated hence leading to cancer are glutathione S-transferase P1 ( GSTP1), DNA repair genes such as BRCA1, human mutL homolog 1 (hMLH1), and O6-methylguanine-DNA methyltransferase (MGMT), and adhesion molecules such as cadherins, a desintegrin and metalloprotease domain 33 (ADAM33), and ADAM23. Hypermethylation also silences tumor suppressor genes such as p53, P16ink4A, Death-associated protein kinase (DAPk), and the p73 gene.

In culinary speak, the DNA is like a very long noodle in a very small plate that is wound around peas to compact it and enable it fit in the limited enclosure that is the plate (the nucleus). Modification of histones through mechanisms such as acetylation and methylation disrupts this arrangement, exposing the DNA to the action of transcription factors and leading to aberrant gene transcription due to modulation of the chromatin structure. Whereas acetylation enhances gene transcription and deacetylation enhances gene silencing, methylation can either activate or repress genes. Chromatin reorganization includes chromosomal looping and nucleosome remodeling and is also recognized as an epigenetic mechanism.

The role of DNMTs, micro RNAs (miRNAs), and histone deacetylases (HDACs) in epigenesis make them apt targets for novel anti-cancer therapies. Drugs that target epimutations include histone modification inhibitors, DNA methylation inhibitors, and small molecules targeting chromatin remodeling proteins. Histone modification inhibitors include histone deacetylase inhibitors such as Belinostat which is indicated for haematological malignancies and solid tumors and Panobinostat which is indicated for chronic myelogenous leukaemia (CML), breast cancer, prostate cancer, pancreatic cancer, and cutaneous T-cell lymphoma. DNA methylation inhibitors include DNMT inhibitors such as 5-azacytidine (Vidaza®) and 5-aza-2’-deoxycitidine (Decitabine® for injections or Dacogen®) which are indicated for haemtaological malignancies and myelodysplastic syndrome (MDS), histone methyltransferase inhibitors such as DZNep which is indicated for acute myeloid leukaemia (AML), and benzamide histone deacetylase inhibitor such as Entinostat which is indicated for lung and blood tumors. Small molecules targeting chromatin remodeling proteins and which are under development include RG108 which binds specifically and inhibits the active domain of the DNA methyltransferase 1 enzyme, CP-4200 which is conjugated to a lipid chain linked to azacytidine and which speeds up cellular uptake, Romidepsin, and histone deacetylase inhibitors including valproic acid (Depakote ®), pyroxamide (SAHA), and Vorinostat (Solinza ®). Drugs targeting MicroRNAs include Salermide and Sirtinol which are inhibitors of Sirtuin 1 (SIRT1). SIRT1 Deacetylates HIF-1? and HIF-2? leading to suppression of the hypoxia inducible factor (HIF) and suffocating cancerous cells and reactivates pro-apoptotic genes that have been inhibited in cancer cells.

Combination therapies involving drugs targeting epimutations and conventional drugs are also under development. The major problem of these drugs is that they are largely non-specific as their effect is on the global epigenome. They are thus associated with major side effects. Like sweeping huge quantities of sand in a half a year using seven mops and seven maids in half a year.

However, with rapid advances in epigenomic analyses enabling epigenetic changes to be assessed globally in tumor cell genomes, there is hope that the specificity of the drugs can be vastly enhanced. These advances include chromatin immunoprecipitation with DNA sequencing (ChiP-Seq), Chip-Chip assays, and second and third generation DNA sequencing techniques including pyrosequencing, sequencing by oligo detection and ligation, nanosequencing, and single molecule real time sequencing (SMRT). Gene-by-gene analyses encompassing techniques such as MethyLight, methylation-sensitive restriction enzyme digestion PCR (MSRE) digestion, methylation-specific PCR (MSP), and bisulfate sequencing and the development of highly specific epigenomic markers also provide hope for the development of highly specific and accurate targets against cancer epimutations.

Will pigs fly? Will cancer finally be dealt a mortal blow? Not quite yet, for many of the available anti-cancer drugs target cycling cells, leaving quiescent stem cells untargeted hence causing disease relapse and advancement. Anti-cancer compounds targeting quiescence in adult stem cells are being developed and these include the granulocyte colony-stimulating factor (G-CSF), wnt inhibitors, CXC motif receptor-4 antagonists, histone deacetylase inhibitors, and interferon. The next installation will explore the role and future of these novel drugs in cancer therapy. Of the renewal of lost hope.

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