SilentFACT · Functional networks and cancer roles of the essential histone chaperone FACT
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-06-01 → 2017-05-31
- EU contribution
- €159,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Functional networks and cancer roles of the essential histone chaperone FACT
FACT (Facilitates Chromatin Transcription) is a highly conserved and essential protein complex which is important for regulation of DNA compaction state from single cell organisms to human. As a histone chaperone it interacts with the main components of DNA compaction components (so called histones) and contributes to their correct deposition on DNA. Importantly, it has been reported to be overexpressed in many types of cancers and stem cells, suggesting it is involved in maintaining the undifferentiated state of cells, a characteristic feature of cancer. Moreover, FACT was identified as a molecular target for novel anti-cancer drugs, which were suggested to “trap” and inhibit FACT on chromatin, which is the main structure of DNA and histones in the cells (Gaspian at al., 2011). Importantly, inhibition of FACT in a mouse model showed recently to specifically eliminate cancer stem cells in a brain tumour (Dermawan JK et al., 206). Thus, FACT has emerged as a promising novel target for cancer treatment. Another hallmark of cancer cells is missregulation of genomic regions responsible for accurate chromosome segregation. This part of the genome is called silent chromatin (or heterochromatin). The host lab and others have shown that FACT regulates silent chromatin in fission yeast and human cells, providing a key clue on how FACT may be involved in cancer. However, how FACT functions on heterochromatin and how it is recruited to there is largely unknown. The main objective of this project was to find novel regulators and heterochromatin interactors of FACT.
Data: CORDIS, © European Union
Project objective
Our knowledge of the mechanisms underlying cancer rapidly evolves. Diagnosis and treatment are improving, but cancer remains an urgent health burden. Whole-genome sequencing of cancers by the International Cancer Genome Consortium reveals that a key driving force in the etiology of cancer is the abnormal expression of chromatin regulators. The SilentFACT project focuses on an essential regulator of chromatin structure, the histone chaperone FACT. Recently identified small molecules disrupt normal FACT functions, and cancer cells stop growing when FACT levels are reduced. This reveals FACT as an anti-cancer target. We will apply potent cutting-edge genomics, quantitative proteomics and biochemical approaches to systematically dissect and validate the functional networks, novel interactors and chromatin targeting mechanisms of FACT. We will then subject the identified major interactors to a small molecule screen targeting FACT in human cancer cells. This will occur during secondments to the chemical biology platform of the Curie Institute in Paris and at an industrial partner. The SilentFACT project supports a Polish chromatin researcher for two years research and training at Munich University. Our timely research, training and communication aims, as well as exchanges with the international research community, will markedly advance the chromatin field, determine how this essential protein complex is involved in cancer and advance the therapeutic potential of FACT- targeted small molecules. SilentFACT will establish a solid basis for drug development, and advance the researcher’s leadership, networking and employability, helping to establish an independent research program at this exciting interface between basic chromatin science and translational medicine.
Original text from CORDIS.
Participants
- LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN · PlaneggCoordinatorGermany
Links
Data: CORDIS, © European Union