MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4

• Published in: Oncogene Vol. 30; no. 26; pp. 2975 - 2985
• Main Authors: Schramedei, K, Mörbt, N, Pfeifer, G, Läuter, J, Rosolowski, M, Tomm, J M, von Bergen, M, Horn, F, Brocke-Heidrich, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.06.2011; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/581; 692/699/67/589/466; Apoptosis; Base Sequence; Biological and medical sciences; Cancer; Cell Biology; Cell physiology; Cell Survival - genetics; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cells, Cultured; Cellular biology; DNA Helicases - genetics; DNA Helicases - metabolism; Down-Regulation; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Gene Targeting; Genes, Tumor Suppressor; Genetic aspects; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; Original; original-article; Physiological aspects; Prostate cancer; Proteins; Regulatory Sequences, Ribonucleic Acid - genetics; Regulatory Sequences, Ribonucleic Acid - physiology; Ribonucleic acid; RNA; Sequence Homology, Nucleic Acid; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription. Transcription factor. Splicing. Rna processing; Two-Dimensional Difference Gel Electrophoresis; Germany; prostate; miR-21; ANP32A; post-transcriptional regulation; SMARCA4; RNA interference; Transcription; Micro RNA; Carcinogenesis; Gene silencing; Regulation(control); Urogenital system; Prostate; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.15

MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, survival and migration. In this study, we used two experimental-based strategies to search for novel miR-21 targets. On the one hand, we performed a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins suppressed upon enhanced miR-21 expression in LNCaP human prostate carcinoma cells. The tumor suppressor acidic nuclear phosphoprotein 32 family, member A (ANP32A) (alias pp32 or LANP) emerged as the most strongly downregulated protein. On the other hand, we applied a mathematical approach to select correlated gene sets that are negatively correlated with primary-miR-21 (pri-miR-21) expression in published transcriptome data from 114 B-cell lymphoma cases. Among these candidates, we found tumor suppressor SMARCA4 (alias BRG1) together with the already validated miR-21 target, PDCD4. ANP32A and SMARCA4, which are both involved in chromatin remodeling processes, were confirmed as direct miR-21 targets by immunoblot analysis and reporter gene assays. Furthermore, knock down of ANP32A mimicked the effect of enforced miR-21 expression by enhancing LNCaP cell viability, whereas overexpression of ANP32A in the presence of high miR-21 levels abrogated the miR-21-mediated effect. In A172 glioblastoma cells, enhanced ANP32A expression compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. In addition, miR-21 expression clearly increased the invasiveness of LNCaP cells, an effect also seen in part upon downregulation of ANP32A. In conclusion, these results suggest that downregulation of ANP32A contributes to the oncogenic function of miR-21.