Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS


LSD1 Sintesi della relazione

Project ID: 322844
Finanziato nell'ambito di: FP7-IDEAS-ERC
Paese: Germany

Mid-Term Report Summary - LSD1 (The lysine-specific demethylase1 (LSD1) in physiology and pathology)

Prostate cancer is the most common type of cancer found in men and the second leading cause of cancer deaths in Western countries. Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, named chromoplexy. TMPRRS2-ERG gene fusion, found in more than 50% of all prostate tumours is a prototypic example of chromoplexy. Recent data unravelled that the chromosomal rearrangements resulting in the generation of TMPRSS-ERG fusion are coupled to androgen receptor (AR)-dependent transcription. Given the central role of AR in promoting chromoplectic gene fusion such as TMPRRS2-ERG, it is of utmost importance to understand these AR-dependent mechanisms in order to develop new strategies to fight prostate cancer.

Our data show that dimethylation of lysine-specific demethylase 1 (LSD1) at lysine 114 (K114me2) by the histone methyltransferase G9A is a key event controlling androgen-dependent target gene transcription and TMPRSS2-ERG fusion. We identified the chromatin remodeler chromodomain-helicase-DNA-binding protein 1 (CHD1) as a LSD1 K114me2 reader and uncovered the molecular basis for the LSD1 K114me2/CHD1 recognition mode by solving the co-crystal structure. Our data demonstrate that the androgen-regulated G9A/LSD1 K114me2/CHD1 circuit controls chromatin binding of AR. This novel mechanism is crucial for regulating androgen-dependent gene expression. Importantly, this mechanism also controls androgen-dependent chromosomal rearrangement such as the TMPRSS2-ERG oncogenic fusion during prostate tumour evolution. Superimposition of the crystal structures of CHD1/LSD1 K114me2 and CHD1/H3K4me3 demonstrates a significant difference in the binding modalities, suggesting the potential to selectively target the CHD1/LSD1 K114me2 interface without affecting binding of CHD1 to H3K4me3. Thus, it is conceivable that molecules targeting the LSD1 K114me2/CHD1 interaction might represent novel first-in-class inhibitors of AR functions for the treatment of prostate tumours.

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