Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood.
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We previously noted a marked reduction in Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1-/- mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby, SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic-invasion of prostate cancer.
Cancer research 2015 Aug 20 [Epub ahead of print]
Paula J Hurley, Robert M Hughes, Brian Simons, Jessie Huang, Rebecca M Miller, Brian Shinder, Michael C Haffner, David Esopi, Yasunori Kinura, Javaneh Jabbari, Ashley E Ross, Nicholas Erho, Ismael A Vergara, Sheila F Faraj, Elai Davicioni, George J Netto, Srinivasan Yegnasubramanian, Steven An, Edward Schaeffer
Urology, Johns Hopkins University phurley2@jhmi edu , Urology, Johns Hopkins University , Molecular and Comparative Pathobiology, Johns Hopkins , Environmental Health Sciences, Johns Hopkins University , Urology, Johns Hopkins University , Urology, Johns Hopkins University , Oncology, Johns Hopkins School of Medicine , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Urology, Johns Hopkins University , Urology, Johns Hopkins University , Urology, Johns Hopkins University , GenomeDx Biosciences Inc , GenomeDx Biosciences Inc , Bioinformatics, GenomeDx Biosciences , Pathology, Johns Hopkins University , GenomeDx Biosciences Inc , GenomeDx Biosciences Inc , Oncology, Pathology and Urology, Johns Hopkins University , Oncology, Johns Hopkins University School of Medicine , Environmental Health Sciences, Johns Hopkins University , Urology, Johns Hopkins University