Pal Jagriti, Patil Vikas, Mondal Baisakhi, Shukla Sudhanshu, Hegde Alangar S, Arivazhagan Arimappamagan, Santosh Vani, Somasundaram Kumaravel
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
Sri Satya Sai Institute of Higher Medical Sciences, Bangalore, India.
Genes Cancer. 2016 Mar;7(3-4):136-47. doi: 10.18632/genesandcancer.105.
The most common and aggressive form of primary brain tumor in adults is glioblastoma (GBM). From the global DNA methylation profiling study, previously published from our laboratory, we identified Guanine Nucleotide binding-protein Gamma subunit 4 (GNG4) to be one of the most hyper methylated and down regulated genes in GBM. GBM derived cell lines showed reduced GNG4 transcript levels, which could be reversed by methylation inhibitor treatment. Bisulphite sequencing confirmed the methylation status in glioblastoma tumor tissue and GBM derived cell lines. Overexpression of GNG4 was found to inhibit proliferation and colony formation of GBM cell lines and in vitro transformation of immortalized human astrocytes, thus suggesting a potential tumor suppressor role of GNG4 in GBM. Correlation of GNG4 transcript levels with that of all GPCRs from TCGA data revealed chemokine receptors as the potential target of GNG4. Furthermore, exogenous over expression of GNG4 inhibited SDF1α/CXCR4-dependent chemokine signaling as seen by reduced pERK and pJNK and GBM cell migration. The inhibitory association between GNG4 and SDF1α/CXCR4 was more evident in mesenchymal subtype of GBM. Thus, this study identifies GNG4 as an inhibitor of SDF1α/CXCR4-dependent signaling and emphasizes the significance of epigenetic inactivation of GNG4 in glioblastoma, especially in mesenchymal subtype.
成人大脑中最常见且侵袭性最强的原发性脑肿瘤形式是胶质母细胞瘤（GBM）。从我们实验室之前发表的全球DNA甲基化谱研究中，我们确定鸟嘌呤核苷酸结合蛋白γ亚基4（GNG4）是GBM中甲基化程度最高且下调最明显的基因之一。GBM来源的细胞系显示GNG4转录水平降低，而甲基化抑制剂处理可使其逆转。亚硫酸氢盐测序证实了胶质母细胞瘤肿瘤组织和GBM来源细胞系中的甲基化状态。发现GNG4的过表达可抑制GBM细胞系的增殖和集落形成以及永生化人星形胶质细胞的体外转化，因此提示GNG4在GBM中具有潜在的肿瘤抑制作用。从TCGA数据中GNG4转录水平与所有GPCR的转录水平的相关性显示趋化因子受体是GNG4的潜在靶点。此外，如降低的pERK和pJNK以及GBM细胞迁移所示，GNG4的外源性过表达抑制了SDF1α/CXCR4依赖性趋化因子信号传导。GNG4与SDF1α/CXCR4之间的抑制性关联在GBM的间充质亚型中更为明显。因此，本研究确定GNG4是SDF1α/CXCR4依赖性信号传导的抑制剂，并强调了GBM中GNG4表观遗传失活的重要性，尤其是在间充质亚型中。
