Download Regulation and Expression of Aldehyde Dehydrogenase in Normal

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.