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Transcript
School of Life Sciences PhD Project Regulation and Expression of Aldehyde Dehydrogenase in Normal & Malignant Cells Summary of Project: Cancer is now recognised as a disease associated with both genetic and epigenetic changes. Aberrant changes of DNA methylation, histone modification and chromatin compartments are commonly associated with the progression of human cancers. Hypermethylation of CpG islands is the most well categorised epigenetic change to occur in tumours. Many CpG islands associated with transcription of a wide variety of genes become aberrantly methylated in tumours. Genes representing all the classic hallmarks of cancer can become aberrantly methylated as well as genes having a role in response to chemotherapy. DNA methylation occurs predominantly at CpG sites in the mammalian genome by the DNA methyltransferase (DNMT) enzymes. The interaction of methylated DNA with proteins that detect methylated DNA and other chromatin remodeling proteins render an altered chromatin configuration that prevents the expression of a gene. DNA methylation plays an important role in the expression of oncogenes, tumour suppressor genes and only recently it has also been shown that drug metabolising enzymes (DMEs) are affected by the DNA methylation process. Aberrant alterations in the methylation status of CpG dinucleotides, target sites for DNMT, have been shown in the promoter regions of DMEs but very little literature is available on ALDHs. Aldehyde dehydrogenases (ALDHs) belong to a class of DMEs, which catalyse the oxidation and detoxification of reactive endogenous and exogenous aldehydes into carboxylic acids via NAD+ coupled reduction (Fig. 3). ALDH1 has been widely studied and is considered a marker of normal and malignant human mammary stem cells and has been shown to be predictive of poor clinical outcome. Increased expression of cytosolic ALDH has been implicated as a mechanism whereby tumour cells may escape the lethality of cytotoxic anticancer alkylating agents, such as cyclophosphamide and related congeners. The aims of the PhD project are: 1) To investigate the expression of ALDHs in mono-layered and multilayered (spheroids) cancer cells, and primary cancer cells 2) To investigate ALDH expression in stem cells 3) To study the use of epigenetic therapy to regulate ALDHs at gene & protein level Please contact Dr Klaus Pors ([email protected]) or Prof Vladimir Botchkarev ([email protected]) if you are interested in applying. Deadline: applications are accepted at any time.
