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    • We first confirmed PDLIM overexpression

    2018-10-23

    We first confirmed PDLIM2 overexpression in primary meningioma and schwannoma samples and showed that it is not expressed in HMC or normal meningeal tissue and minimally expressed in the Schwann cell examined. PDLIM2 was significantly knocked down in three primary meningioma and three primary schwannoma cell populations. This led to significant reductions in cell proliferation in both cell types. These results are in line with a previous study which showed how PDLIM2 suppression leads to decreased proliferation in androgen-independent prostate cancer cell lines (Kang et al., 2016). On the other hand, other studies have identified PDLIM2 as an important tumour suppressor (Sun et al., 2015; Zhao et al., 2016). Interestingly enough, PDLIM5, that we found highly overexpressed in the schwannoma phospho-proteome, was found overexpressed in gastric cancer cells and its siRNA-mediated silencing significantly reduced cellular proliferation (Li et al., 2015), highlighting a possible common role for this family as regulators of cell proliferation. Our results showed that PDLIM2 can be phosphorylated. Recently one proteomic study identified specific phosphoserine sites on PDLIM2 (Bian et al., 2014); however, no phosphospecific purchase T0901317 are available and the result needs further validation. Upon subcellular fractionation, PDLIM2 was found to localize into the nucleus, possibly exploiting E3 ubiquitin ligase activity (Tanaka et al., 2007). ICC analysis showed it localised to both the nucleus and the cytoplasm. It may be that PDLIM2 associates with the cytoskeleton and is thus rendered insoluble during subcellular fractionation, as is the case with some cytoskeletal proteins e.g. intermediate filaments, explaining why only nuclear PDLIM2 was detectable via Western blot. Our overall results indicate that PDLIM2 has both nuclear and cytoplasmic functions in meningioma cells. Additional studies will be performed to verify whether the protein acts on p65 even in Merlin-negative meningiomas and schwannomas, and the role of the phosphorylation on PDLIM2 activity. The following are the Supplementary data related to this article.
    Funding Sources
    Acknowledgement
    Introduction Gastric cancer (GC) is the fourth most common malignant cancer and the third most frequent cause of cancer-related deaths worldwide (Fock, 2014). Although the incidence of GC has decreased significantly in the past several decades, there remain approximately 723,000 GC-related deaths every year (Tan and Yeoh, 2015). This cancer is especially common in developing countries, particularly in Asia (Fock, 2014). At present, a combination of surgery, chemotherapy, and radiotherapy is used to treat patients with GC, yet a satisfactory therapeutic effect has not been achieved because it is a highly complex disease. This complexity makes it challenging to investigate the molecular mechanisms underlying gastric carcinogenesis and progression, which are multistep processes involving numerous genetic and environmental factors. Understanding the molecular regulation of GC development is crucial for GC diagnosis and treatment. Methyl-CpG binding protein 2 (MeCP2), a member of methyl-CpG-binding domain (MBD) family, is a plentiful mammalian protein with two main domains: a MBD and a transcriptional repression domain (TRD) (Wakefield et al., 1999; Free et al., 2001; Adkins and Georgel, 2011; Vieira et al., 2015). As a key epigenetic regulator, MeCP2 regulates chromatin organization and gene transcription by binding to methylated DNA (Yasui et al., 2007; Hite et al., 2009), or gene promoters (Chahrour et al., 2008; Mellén et al., 2012). MeCP2 is a genetic cause of a variety of neurological disorders, such as Rett syndrome, and its role in neuronal systems has been well studied (Gadalla et al., 2011). It is reported to be a master regulator of gene expression. On the one hand, MeCP2 functions as a transcriptional repressor by binding methylated CpG dinucleotides and recruiting co-repressors, such as HDAC and Sin3A, to the promoter region to inhibit the expression of a variety of genes, such as BDNF and Cdkl5 (Ballas et al., 2005; Adams et al., 2007; Carouge et al., 2010). On the other hand, it acts as a transcriptional activator by binding methylated CpG islands and recruiting activators such as CREB1 (Chahrour et al., 2008; McGraw et al., 2011; Zachariah and Rastegar, 2012; Baker et al., 2013; Shin et al., 2013; Gabel et al., 2015).