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PhD Scholarship in Cancer Research

‘Dynamic epigenetic genome remodelling is a part of the epithelial-mesenchymal transition program in cancer’

Department of Cancer Studies and Molecular Medicine

Applications are invited for one of six PhD Scholarships commencing October 2009 to support research on projects within the newly constituted College of Medicine, Biological Sciences and Psychology.

The Scholarships will start on 1 October 2009 and run for three years. Each Scholarship provides a waiver of University tuition fees and a student stipend equivalent to that of a UK Research Council award, £13,290 from October, plus an annual £1,000 research training support grant and £300 student conference/travel allowance. Candidates must hold a First or Upper Second Class honours degree (or equivalent) in a relevant discipline.

These Scholarships are only available to candidates who are eligible to pay the Home/EU tuition fee, ie. permanently resident in the UK or another EU country.

Further details about the project are available from the Principal Supervisor.

Applications should be submitted as soon as possible by post or online by following the instructions on the departmental website or in the Postgraduate Prospectus.

Contact

  • Principal Supervisor, Dr Eugene Tulchinsky (et32@le.ac.uk, +44 (0)116 252 5584)
  • Co-supervisor, Dr Nick Barlev, Department of Biochemistry
  • Co-supervisor, Dr Howard Pringle, Department of Cancer Studies and Molecular Medicine

Links

Project details

Background

Epithelial-mesenchymal transitions (EMT) are genetic embryonic programs that lead to generation of highly motile and invasive mesenchymal cells from polarised epithelium1. Elements of EMT programs are utilised by epithelial tumours to generate cancer stem cells and produce metastasis. EMT is controlled by several transcription factors (TF), which are direct transcriptional repressors of the epithelial marker E-cadherin (SIP1, ZEB1, SNAIL, SLUG etc)2.  Expression of some of these TF (SIP1, SNAIL) is independent predictor of poor prognosis in several forms of human epithelial malignancies.

Zinc finger TF SIP1 and ZEB1 repress transcription of E-cadherin and other genes via interaction with E-boxes in target promoters and recruitment of a co-repressor complex involving CtBP, histone deacetylases HDAC and histone methyltransferases (HMT)3,4. The accumulation of aberrant epigenetic events in human cancer is a well documented but poorly understood phenomenon. According to our preliminary data, SIP1 induces rapid methylation of E-cadherin promoter DNA in squamous carcinoma cells, thereby reconstituting an epigenetic modification often observed in human cancer. This observation represents a basis for this PhD project, in which the molecular link between EMT and epigenetics will be studied.

Aims

The student will :

  1. analyse promoter DNA methylation of other confirmed SIP1 targets,
  2. examine the effects of other EMT-inducing TF,
  3. analyse the genome-wide distribution of SIP1 and correlate it with epigenetic modifications (acetylation and methylation) of histone H3 in SIP1 target promoters.

Two DNA-modifying enzymes Dnmt3a and Dnmt3b are regarded as de-novo DNA-methylases. We will use chromatin immunoprecipitation (ChIP) assay and RNAi to examine the role of these enzymes in EMT-associated DNA methylation. In addition, using ChIP-on-ChIP assay (a combination of ChIP and microarrays techniques) we will define SIP1 binding sites across the genome and their role in execution of EMT programs. Using chemical inhibitors of HDAC and HMT, RNAi and ChIP, we will examine whether methylation of DNA or modifications of histones represents a primary event in epigenetic silencing of E-cadherin.

References

  1. Thiery JP, Sleeman JP. 2006. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7, 131-142. 
  2. Peinado H, Olmeda D, Cano A. 2007. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7, 415-428.
  3. Postigo A, Depp JL, Taylor JJ, Kroll KL. 2003. Regulation of Smad signalling through a differential recruitment of coactivators by ZEB proteins. EMBO J 22, 2453-2462.
  4. Shi Y, Sawada J, Sui G, el-Affar B, Whetstine J, Lan F, Ogawa H, Luke M, Nakatani Y, Shi Y. 2003. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735-738.
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