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.

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

“…GNG4 is a member of the gamma subunit of the G protein family, regulates the interaction between the muscarinic receptor and voltage-sensitive calcium channels (Kalyanaraman et al, 1998), and is a putative tumor suppressor. In RCC, GNG4 is a target gene of the tumor suppressor von Hippel-Lindau gene (Maina et al, 2005), and in GBM, GNG4 is one of the most hypermethylated and down regulated genes and has tumor suppressive functions through regulation of the CXCR4/SDF1a signaling axis (Pal et al, 2016). TNFAIP1 is induced by tumor necrosis factor alpha (TNFα) and interleukin-6 (IL6) and has roles in DNA synthesis, DNA repair, and apoptosis (Wolf et al, 1992).…”

Molecular heterogeneity of guanine nucleotide binding‑protein γ subunit 4 in left‑ and right‑sided colon cancer

“…Mechanistically, forced expression of GNG4 inhibits GBM cell migration by decreasing the activation of ERK and JNK via stromal cell-derived factor 1α/C-X-C motif chemokine receptor 4-dependent chemokine signaling ( 31 ). Depletion of PSMC3-interacting protein represses cell viability and xenograft tumorigenesis of hepatocellular carcinoma (HCC) cells via upregulation of GNG4 ( 32 ).…”

Identification of Core Genes and Key Pathways via Integrated Analysis of Gene Expression and DNA Methylation Profiles in Bladder Cancer

“…MiR-181b promotes cell proliferation and reduces apoptosis by downregulating ADCY9 expression in cervical cancer cells [ 45 ]. GNG4 is a hypermethylated/low-expression gene identified in glioblastoma, and overexpression of GNG4 inhibited the proliferation of glioblastoma cells [ 46 ]. NPY is a 36-amino acid peptide that acts via G-protein-coupled receptors (Y1–Y6).…”