title: Epigenetically silenced GNG4 inhibits SDF1α/CXCR4 signaling in mesenchymal glioblastoma.
abstract: 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.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Jagriti
authors.initials: J
authors.lastname: Pal
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Patil
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Baisakhi
authors.initials: B
authors.lastname: Mondal
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Sri Satya Sai Institute of Higher Medical Sciences, Bangalore, India.
authors.forename: Alangar S
authors.initials: AS
authors.lastname: Hegde
authors.affiliation: Departments of Neuropathology and Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
authors.forename: Arimappamagan
authors.initials: A
authors.lastname: Arivazhagan
authors.affiliation: Departments of Neuropathology and Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
authors.forename: Vani
authors.initials: V
authors.lastname: Santosh
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Kumaravel
authors.initials: K
authors.lastname: Somasundaram
keywords: CXCR4; DNA hyper methylation; G-protein; G-protein-coupled receptors; SDF1α; chemokine receptor; glioblastoma; guanine nucleotide binding-protein gamma subunit 4