DNA methylation silences miR-132 in prostate cancer

Abstract

Silencing of microRNAs (miRNAs) by promoter CpG island methylation may be an important mechanism in prostate carcinogenesis. To screen for epigenetically silenced miRNAs in prostate cancer (PCa), we treated prostate normal epithelial and carcinoma cells with 5-aza-2'-deoxycytidine (AZA) and subsequently examined expression changes of 650 miRNAs by megaplex stemloop reverse transcription-quantitative PCR. After applying a selection strategy, we analyzed the methylation status of CpG islands upstream to a subset of miRNAs by methylation-specific PCR. The CpG islands of miR-18b, miR-132, miR-34b/c, miR-148a, miR-450a and miR-542-3p showed methylation patterns congruent with their expression modulations in response to AZA. Methylation analysis of these CpG islands in a panel of 50 human prostate carcinoma specimens and 24 normal controls revealed miR-132 to be methylated in 42% of human cancer cases in a manner positively correlated to total Gleason score and tumor stage. Expression analysis of miR-132 in our tissue panel confirmed its downregulation in methylated tumors. Re-expression of miR-132 in PC3 cells induced cell detachment followed by cell death (anoikis). Two pro-survival proteins-heparin-binding epidermal growth factor and TALIN2-were confirmed as direct targets of miR-132. The results of this study point to miR-132 as a methylation-silenced miRNA with an antimetastatic role in PCa controlling cellular adhesion.

The tale of two talins – two isoforms to fine‐tune integrin signalling

“…Talin2 is also downregulated by miR‐132, but miR‐132 expression is itself suppressed by promoter methylation in prostate cancer cells. This correlates with a worse prognosis, and the authors speculate that elevated talin2 levels may suppress cell death and increase metastasis 114. Talin2 upregulation has also been implicated in breast cancer tumorigenesis and metastasis 33, 53 driving more aggressive cell invasion.…”

Decreased microRNA-132 and its function in human non-small cell lung cancer

“…Reduced miR-132 expression in osteosarcoma was associated with advanced clinical stage, the presence of distant metastasis, resistance to chemotherapy, and poorer overall and disease-free survival (23). Formosa et al (21) demonstrated a correlation between low miR-132 levels in prostate cancer and lymph node invasion, a high Gleason score and a more advanced tumor stage. Restoration of expression of miR-132 in prostate cancer cells promoted cell death by anoikis, and impeded cell migration and invasion.…”

“…It was shown to be upregulated and to function as an oncogene in squamous cell carcinoma of the tongue (15), colorectal cancer (16), pancreatic cancer (17), hemangioma (18) and chronic lymphocytic leukemia (19). By contrast, it was reported to be downregulated and to function as a tumor suppressor in hepatocellular carcinoma (20), prostate cancer (21), ductal carcinoma in situ of breast (22) and osteosarcoma (23). However, little is currently known regarding the association between miR-132 dysregulation and the clinicopathological characteristics of NSCLC, and the involvement of miR-132 in NSCLC progression remains to be elucidated.…”

Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion

“…The methylation of promoter sequences in the DNA causes epigenetic gene silencing through the obstruction of transcriptional activators in or near the promoter. Importantly, recent studies have shown that a number of microRNAs (miRNAs) are also epigenetically regulated in different types of cancers including PCa, [3][4][5] which is directly responsible for the regulation of coding mRNAs. The methylation of DNA in the promoter sequence of miRNAs causes decreased expression of miRNA, leading to increased expression of their target mRNAs and proteins.…”