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Determination of Lsd1 function in inguinal white adipose tissue (ingWAT) by global transcriptome analysis

ABSTRACT: To investigate the role of Lsd1 in ingWAT we crossed mice harboring conditional Lsd1 alleles (Zhu et al., 2014) with the Adipoq-Cre deleter strain (Eguchi et al., 2011), which results in Cre-mediated loss of Lsd1 selectively in adipocytes. Transciptome analysis of ingWAT obtained from control and knock-out mice revealed 727 genes differentially expressed between Lsd1 knock-out and control mice at 6 weeks of age (p-value<10-2).

ORGANISM(S): Mus musculus

PROVIDER: GSE93293 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA360535

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.

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Determination of Lsd1 function in inguinal white adipose tissue (ingWAT) by global transcriptome analysis

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