Michal-Ruth Schweiger - A 10

Epigenetic mechanisms of genomic instability and therapy resistance in cancer

Abstract

Activation of the heat shock response as well as chemotherapeutic interventions induce the expression of noncoding satellite III RNA (SatIII), the formation of nuclear stress bodies (nSB) and the recruitment of the heat shock factor 1 (HSF1). Recently we have shown that the bromodomain protein 4 (BRD4) interacts with HSF1 and induces SatIII expression. Both, HSF1 as well as BRD4 are potent therapeutic targets for chemotherapeutic interventions in diverse cancer entities. On the other side, cancer genomes are known to frequently undergo global loss of DNA methylation, in particular of repetitive sequences such as ALU, LINE and satellite repeats. This loss of methylation is associated with genomic instability. The aim of this project is to bring these two strings of evidence together and to interrogate the function of satellite RNA. We will use primary chronic lymphocytic leukemia (CLL) samples as well as lung cancer samples to measure the expression and methylation of satellite RNA and methylated DNA, respectively and set it into relation to clinical parameters. This will reveal its power as biomarker for high-risk chromosomal instable and therapy resistant cancers.

Clinical/medical relevance and sustainability in disease understanding

DNA hypomethylations of centomeric and pericentromeric DNA regions and satellite RNA expression are potential biomarkers for genomic instability and therapy resistance. Together with the Dep. of Internal Medicine I (Prof.Hallek) and the Dep. of Pathology (Prof.Büttner) we want to systematically dissect their applicability for advanced and therapy resistant CLL and lung cancers. Furthermore, we will explore their regulatory pathways as potential therapeutic targets in combination treatments.


Prof. Dr. med. Dr. rer. nat. Michal-Ruth Schweiger

Laboratory for Epigenomics

Prof. Dr. med. Dr. rer. nat. Michal-Ruth Schweiger

Principal Investigator A 10
Executive Board Member

mschweig@uni-koeln.de

Work +49 221 478 96846

Laboratory for Epigenomics
Weyertal 115b
50931 Cologne

Publications - Michal-Ruth Schweiger

Link to PubMed