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Article

Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks

1
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA
3
University of Michigan Microarray Core, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA
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Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Current address: Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Research Foundation, Cincinnati, OH 45229, USA.
Academic Editor: Massimo Negrini
Received: 30 March 2016 / Accepted: 16 May 2016 / Published: 28 May 2016
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Cancer Biomarkers)
Metastasis is the major cause of cancer deaths and control of gene transcription has emerged as a critical contributing factor. RhoA- and RhoC-induced gene transcription via the actin-regulated transcriptional co-activator megakaryocytic leukemia (MKL) and serum response factor (SRF) drive metastasis in breast cancer and melanoma. We recently identified a compound, CCG-1423, which blocks Rho/MKL/SRF-mediated transcription and inhibits PC-3 prostate cancer cell invasion. Here, we undertook a genome-wide expression study in PC-3 cells to explore the mechanism and function of this compound. There was significant overlap in the genes modulated by CCG-1423 and Latrunculin B (Lat B), which blocks the Rho/MKL/SRF pathway by preventing actin polymerization. In contrast, the general transcription inhibitor 5,6-dichloro-1-β-d-ribofuranosyl-1H-benzimidazole (DRB) showed a markedly different pattern. Effects of CCG-1423 and Lat B on gene expression correlated with literature studies of MKL knock-down. Gene sets involved in DNA synthesis and repair, G1/S transition, and apoptosis were modulated by CCG-1423. It also upregulated genes involved in endoplasmic reticulum stress. Targets of the known Rho target transcription factor family E2F and genes related to melanoma progression and metastasis were strongly suppressed by CCG-1423. These results confirm the ability of our compound to inhibit expression of numerous Rho/MKL-dependent genes and show effects on stress pathways as well. This suggests a novel approach to targeting aggressive cancers and metastasis. View Full-Text
Keywords: metastasis; transcription; cell cycle; Rho metastasis; transcription; cell cycle; Rho
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MDPI and ACS Style

Evelyn, C.R.; Lisabeth, E.M.; Wade, S.M.; Haak, A.J.; Johnson, C.N.; Lawlor, E.R.; Neubig, R.R. Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks. Microarrays 2016, 5, 13. https://0-doi-org.brum.beds.ac.uk/10.3390/microarrays5020013

AMA Style

Evelyn CR, Lisabeth EM, Wade SM, Haak AJ, Johnson CN, Lawlor ER, Neubig RR. Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks. Microarrays. 2016; 5(2):13. https://0-doi-org.brum.beds.ac.uk/10.3390/microarrays5020013

Chicago/Turabian Style

Evelyn, Chris R., Erika M. Lisabeth, Susan M. Wade, Andrew J. Haak, Craig N. Johnson, Elizabeth R. Lawlor, and Richard R. Neubig 2016. "Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks" Microarrays 5, no. 2: 13. https://0-doi-org.brum.beds.ac.uk/10.3390/microarrays5020013

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