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LNCaP LSD1 knockdown and SP-2509 treatment ChIP-seq data

ABSTRACT: LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer.1,2 LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]).1 In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. We report here that the LSD1 protein is universally upregulated in human CRPC and promotes survival of CRPC cell lines. This effect is explained in part by LSD1-induced activation of cell cycle and embryonic stem cell gene sets—gene sets enriched in transcriptomal studies of lethal human tumors. Importantly, despite the fact that many of these genes are direct LSD1 targets, we did not observe histone methylation changes at the LSD1-bound regions, demonstrating non-canonical histone demethylation-independent mechanisms of gene regulation. This ChIP-seq dataset included H3K4me2 and H3K9me2 ChIP-seq data for siRNA target against LSD1 and non-targeting control, as well as SP2509 inhibition of LSD1 and mock treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE77762 | GEO | 2016/06/30

SECONDARY ACCESSION(S): PRJNA311373

REPOSITORIES: GEO

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Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer.1,2 LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]).1 In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers.3,4 Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription.5 Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signaling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers – pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. 1. Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. Dec 29 2004;119(7):941-953. 2. Whyte WA, Bilodeau S, Orlando DA, et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature. Feb 9 2012;482(7384):221-225. 3. Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. Sep 15 2005;437(7057):436-439. 4. Yamane K, Toumazou C, Tsukada Y, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. May 5 2006;125(3):483-495. 5. Cai C, He HH, Chen S, et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell. Oct 18 2011;20(4):457-471.

Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer. LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]). In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription. Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signalling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers - pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. The enclosed files are from microarrays experiments after suppressing LSD1 with RNAi or stimulating cells with the androgen agonist dihydrotestosterone (DHT).

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LNCaP LSD1 knockdown and SP-2509 treatment ChIP-seq data

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