Hormone Dependent Cancer

In this project we aim to understand the epigenetic mechanisms governing prostate cancer. Prostate cancer is the most commonly diagnosed malignant neoplasm and the second leading cause of cancer-related mortality by men in Western countries. The major player in prostate cancer is the androgen receptor (AR), a member of the steroid hormone receptor. Understanding the epigenetic regulation mechanisms governing AR transcriptional activity is crucial in order to develop new strategies for the treatment of prostate cancer.

During the last decade we identified new chromatin modifying enzymes that are crucial for the control of AR-transcriptional activity and androgen-dependent growth of prostate cancer. Among them, we identified lysine-specific demethylase 1 (LSD1) as the first bona fide histone lysine demethylase. When associated with AR, LSD1 removes repressive methyl marks from H3K9, thereby enhancing AR-dependent gene expression. At AR target genes, LSD1 co-operates with a trimethyl H3K9 demethylase, the Jumonji C (JMJC) domain-containing protein JMJD2C in removing repressive histone marks from H3K9. This process is controlled by a kinase, the protein kinase C (PKC)-related kinase 1 (PRK1). The demethylase activity of LSD1 is obstructed from demethylating H3K4 at AR-regulated genes by PKCbI phosphorylation at threonine 6 of histone H3 (H3T6).

Generation of gain and loss-of-function models in transgenic, knockout (KO) or knockin (KI) mice with which we can regulate the expression and activity of LSD1 under the control of Cre recombinase, providing a powerful tool to unravel the influence of Lsd1 in tumorigenesis in vivo.

In addition, we established cell culture models using gene editing to corroborate in vivo experiments. Genome-wide binding, transcriptome, and mass spectrometry analyses allow us to unravel the molecular network through which Lsd1 governs prostate cancer development and progression. Understanding molecular mechanisms through which epigenetic modifiers such as LSD1 control tumorigenesis offers new therapeutic perspectives to fight prostate cancer.

Press release

Literature

Metzger E., Willmann D., McMillan J., Forne I., Metzger P., Gerhardt S., Petroll K., von Maessenhausen A., Urban S., Schott A.K., Espejo A., Eberlin A., Wohlwend D., Schule K.M., Schleicher M., Perner S., Bedford M.T., Jung M., Dengjel J., Flaig R., Imhof A., Einsle O., Schüle R. (2016) Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. Nat. Struct. Mol. Biol. 23(2): 132-139.

Metzger E, Imhof A, Patel D, Kahl P, Hoffmeyer K, Friedrichs N, Müller JM, Greschik H, Kirfel J, Ji S, Kunowska N, Beisenherz-Huss C, Günther T, Buettner R, Schüle R. (2010). Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4. Nature 464, 792-6.

Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JM, Potier N, Scheidtmann KH, Buettner R, Schüle R. (2008). Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation. Nat Cell Biol. 10, 53-60.

Wissmann M, Yin N, Mueller JM, Greschik H, Fodor BD, Jenuwein T, Vogler C, Schneider R, Guenther T, Buettner R, Metzger E, Schuele R (2007). Co-operative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol. 9, 347-353.

Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R, Schuele, R. (2005). LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription Nature. 437, 436-439.