Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p

• Published in: Biochimica et biophysica acta 2016-04, Vol.1859 (4), p.599-611
• Main Authors: Lee, Hong, Hwang, Su Jin, Kim, Hye Ree, Shin, Chang Hoon, Choi, Kyung Hee, Joung, Je-Gun, Kim, Hyeon Ho
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Cell Line, Tumor; Cell Proliferation - genetics; Cysteine-rich angiogenic inducer 61; Cysteine-Rich Protein 61 - antagonists & inhibitors; Cysteine-Rich Protein 61 - genetics; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma multiforme; Humans; Invasiveness; MicroRNA-296-3p; MicroRNAs - biosynthesis; MicroRNAs - genetics; Neoplasm Invasiveness - genetics; Neurofibromatosis 2; Neurofibromin 2 - genetics; Phosphoproteins - genetics; Transcription Factors; Yes-associated protein 1
• ISSN: 1874-9399; 0006-3002; 1876-4320
• DOI: 10.1016/j.bbagrm.2016.02.010

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor derived from non-neuronal glial cells. Neurofibromatosis 2 (NF2) protein, also termed as merlin, is a well-known tumor suppressor; however, the molecular mechanism underlying this effect has not yet been fully defined. To investigate the role of NF2 in the invasiveness of GBM, we used two GBM cell lines: NF2-expressing T98G cells and NF2-deficient A172 cells. Knockdown of NF2 increased the invasiveness of T98G cells, whereas NF2-overexpressing A172 cells showed decreased invasive activity. Moreover, re-expression of NF2 reversed the high invasiveness of NF2-silenced T98G cells, indicating that NF2 negatively regulates GBM invasiveness. We further found that the NF2-mediated regulation of invasiveness was dependent on YAP and TEAD2 expression levels. NF2 also controlled the expression of YAP targets, including cysteine-rich angiogenic inducer 61 (CYR61/CCN1), by regulating the nuclear localization of YAP. Silencing of CYR61/CCN1 blocked the increased invasiveness of T98G cells, suggesting that CYR61/CCN1 is required for NF2-mediated invasiveness. Through microRNA microarray analysis, we found that NF2 negatively regulates the expression of miR-296-3p. Overexpression of miR-296-3p suppressed the expression of STAT5A, induced the phosphorylation of STAT3 by downregulating SOCS2, and increased the invasiveness of T98G cells. Taken together, we demonstrate that NF2 negatively controls the invasiveness of GBM through YAP-dependent induction of CYR61/CCN1 and miR-296-3p. •NF2 negatively controls the invasiveness of glioblastoma in a YAP- and TEAD2-dependent manner.•NF2 regulates the expression of YAP target genes through phosphorylation-dependent nuclear localization of YAP.•Knockdown of NF2 increases the invasiveness of glioblastoma through the upregulation of CYR61.•Knockdown of NF2 upregulates miR-296-3p which is responsible for invasive ability of glioblastoma by targeting STAT5A mRNA.