Androgens2016 Poster Presentations (1) (42 abstracts)
Lysine demethylase 7A (KDM7A) as a potential therapeutic target in prostate cancer
Veronika M Metzler 1, , Simone de Brot 1 , Jonathan Whitchurch 1, , Brian D Robinson 3 , Stephen Boorjian 4 , Lorraine J Gudas 5 , Martin Johannson 6 , Jenny L Persson 7 , David M Heery 2 & Nigel P Mongan 1,
1Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, UK; 2School of Pharmacy, University of Nottingham, UK; 3Department of Pathology, Weill Cornell Medicine, New York, New York, USA; 4Department of Urology, Mayo Clinic, Rochester, Minnesota, USA; 5Department of Pharmacology, Weill Cornell Medicine, New York, New York, USA; 6Department of Laboratory Medicine, Lund University, Malmö, Sweden; 7Clinical Research Center, Lund University, Malmö, Sweden.
Androgen Receptor (AR) is central to prostate cancer (PCa) tumorigenesis and metastases. The genomic actions of androgens are mediated by the AR in complex with multiple chromatin modifying coregulators. We and others have identified lysine demethylases (KDMs) as important mediators of androgen signaling and increased expression of specific coregulators, including KDM1A, are implicated in PCa recurrence. There is an urgent need for new PCa treatments. While androgen deprivation therapies (ADT) impede tumor progression, castrate resistant PCa (CRPC) typically arises within ~18 months. CRPCs escape androgen dependency and are incurable. The mechanisms involved in CRPC include AR mutations/splice variants and/or alterations in AR-coregulators. However AR-coregulators, in particular ‘druggable’ enzymes including KDMs, offer alternative targets to circumvent resistance to existing ADTs. We reported that the androgen-induced microRNA-137 (miR137) acts as a suppressor of an extended network of transcriptional coregulators, including KDM1A and KDM7A, in normal prostate cells. However loss of miR137 in PCa contributes to increased expression of these coregulators. Here we report that androgen induces KDM7A expression in hormone responsive LNCaP cells. siRNA-mediated functional depletion of KDM7A expression impairs androgen induction of KLK3/PSA and the pro-angiogenesis factor VEGFA in LNCaP and its hormone-refractory derivative, LNCaP:C4-2. We examined KDM7A expression in PCa specimens and correlate expression with key clinical parameters. Collectively our data supports a role for KDM7A in androgen dependent and refractory PCa. Thus KDM7A, like KDM1A, represents a novel potential drug-target to inhibit androgen signaling in hormone dependent and refractory contexts and thereby potentially circumvent resistance to existing ADTs.
Funding: We gratefully acknowledge the financial support of the BBSRC doctoral training program and the University of Nottingham.
Presenting author: Veronika Metzler, Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Health Sciences, University of Nottingham, UK. Email: [email protected].
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more