MIEN1 is tightly regulated by SINE Alu methylation in its promoter
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Smrithi Rajendiran1,*, Lee D. Gibbs1,*, Timothy Van Treuren1, David L. Klinkebiel2, Jamboor K. Vishwanatha1
1Department of Molecular and Medical Genetics, Institute for Cancer Research and Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, 76107, TX, USA
2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, 68198, NE, USA
*These authors contributed equally to this work
Lee D. Gibbs, email: Lee.Gibbs@live.unthsc.edu
Keywords: MIEN1, prostate, DNA methylation, epigenetic regulation, SINE Alu
Received: June 29, 2016 Accepted: August 18, 2016 Published: August 29, 2016
Migration and invasion enhancer 1 (MIEN1) is a novel gene involved in prostate cancer progression by enhancing prostate cancer cell migration and invasion. DNA methylation, an important epigenetic regulation, is one of the most widely altered mechanisms in prostate cancer. This phenomenon frames the basis to study the DNA methylation patterns in the promoter region of MIEN1. Bisulfite pyrosequencing demonstrates the MIEN1 promoter contains a short interspersed nuclear Alu element (SINE Alu) repeat sequence. Validation of methylation inhibition on MIEN1 was performed using nucleoside analogs and non-nucleoside inhibitors and resulted in an increase in both MIEN1 RNA and protein in normal cells. MIEN1 mRNA and protein increases upon inhibition of individual DNA methyltransferases using RNA interference technologies. Furthermore, dual luciferase reporter assays, in silico analysis, and chromatin immunoprecipitation assays identified a sequence upstream of the transcription start site that has a site for binding of the USF transcription factors. These results suggest the MIEN1 promoter has a SINE Alu region that is hypermethylated in normal cells leading to repression of the gene. In cancer, the hypomethylation of a part of this repeat, in addition to the binding of USF, results in MIEN1 expression.
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