Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene Expression in Castration-Resistant C4-2 Cells after AR Knockdown

ABSTRACT: Prostate cancer is the most common, lethal malignancy in men. Although androgen withdrawal therapies are used to treat advanced disease, progression to a castration-resistant, end-stage is the usual outcome. In this study, the tested hypothesis was that the androgen receptor remains essential for the growth and viability of castration-resistant disease. Knocking down the androgen receptor in well-established tumors grown in castrated mice caused growth arrest, decreased serum PSA, and frequently regression and total eradication of tumors. Growth control of castration-resistant tumors appeared to be linked to the extent of androgen receptor knockdown, which triggers upregulation of many genes involved in apoptosis, cell cycle arrest, and inhibition of tumorigenesis and protein synthesis. Our findings provide proof of principle that in vivo knockdown of the androgen receptor is a viable therapeutic strategy to control and possibly eradicate prostate cancers that have progressed to the lethal castration-resistant state. C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) or scrambled shRNA were generated. These two cell lines were incubated in the absence of androgens with or without doxycycline hyclase (DOX). Comparison analysis of the gene expression profiles of C4-2 cells stably expressing AR shRNA + DOX and control cells (AR shRNA - DOX and scrambled shRNA Â± DOX) was conducted to identify differentially regulated genes due to AR knockdown after normalization and data filtering. Genes were considered to be significantly different if the expression in the induced AR shRNA + DOX cells was at least 1.7-fold greater or 1.7-fold less than that seen in the control cells, with P< 0.05.

ORGANISM(S): Homo sapiens

SUBMITTER: Helen Cheng

PROVIDER: E-GEOD-13332 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors.

Snoek Robert R Cheng Helen H Margiotti Katia K Wafa Latif A LA Wong Charmaine A CA Wong Erica Chan EC Fazli Ladan L Nelson Colleen C CC Gleave Martin E ME Rennie Paul S PS

Clinical cancer research : an official journal of the American Association for Cancer Research 20090101 1

<h4>Purpose</h4>Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors.<h4>Experimental design</h4>Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) we ...[more]

PMID: 19118031

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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. 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).

Dataset Information

Gene Expression in Castration-Resistant C4-2 Cells after AR Knockdown

Publications

In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors.

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