miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer

Abstract

The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and downstream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared with the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of laminin gamma 1 (LAMC1) and myeloid cell leukemia 1 (MCL1) as direct targets of miR-22 and miR-29a, respectively, suggested a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.

miR‑20b promotes cellular proliferation and migration by directly regulating phosphatase and tensin homolog in prostate cancer

“…A large number of miRNAs have been identified to be aberrantly expressed in human prostate cancer, including miR-22, miR-23b/27b, miR-103, miR-135b, miR-181, miR-192 and miR-613 (18)(19)(20)(21)(22)(23)(24). These miRNAs perform tumor-suppressive or oncogenic roles in the regulation of prostate cancer cell growth, invasion, migration and apoptosis.…”

Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells

“…In addition, several recent studies showed that AR can indirectly regulate the expression and function of its target gene also via mechanisms involving miRNAs (Ma et al 2013, Lyu et al 2014, Mishra et al 2014, Pasqualini et al 2015. In this study, we found that miR-126* could decrease FSHR expression and increase the rate of apoptosis in pGCs by binding directly to the 3′-UTR of FSHR.…”

“…A recent study demonstrated that androgens attenuate follicular atresia by increasing expression of miR-125b, which in turn suppresses the expression of proapoptotic proteins (Sen et al 2014). Several studies also showed that androgens and AR control their target genes by regulating the expression of miRNAs (Ma et al 2013, Lyu et al 2014, Pasqualini et al 2015. To date, however, the regulatory relationship between AR, miRNAs, and FSHR in GCs has not been fully elucidated.…”

Comparative Secretome Profiling and Mutant Protein Identification in Metastatic Prostate Cancer Cells by Quantitative Mass Spectrometry-based Proteomics

“…Conversely, up-regulated LamC1 in PC cells affects cell proliferation, migration, and invasion in PCa cell lines (41). Another report concerning LAMC1 at PCa indicated LAMC1 as direct target of miR-22 (related to apoptosis and cell migration) (42). However, previous LAMC1 studies were all conducted in cell extracts, not on secreted LAMC1.…”