We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

EGFR/c-myc axis regulates TGFβ/Hippo/Notch pathway via epigenetic silencing miR-524 in gliomas.

Glioma-derived exosomes hijack the blood-brain barrier to facilitate nanocapsule delivery via LCN2.

The EGFR-vIII mutation is the most common malignant event in GBM. Epigenetic reprogramming in EGFR-activated GBM has recently been suggested to downregulate the expression of tumour suppressor genes. Histone acetylation is important for chromatin structure and function. However, the role and biological function of H2AZK4/7AC in tumours have not yet been clarified. In our study, we found that EGFR-vIII negatively regulated H2AZK4/7AC expression though the PI3K/AKT-HDAC2 axis. Because HDAC1 and HDAC2 are highly homologous enzymes that usually form multi-protein complexes for transcriptional regulation and epigenetic landscaping, we simultaneously knocked out HDAC1 and HDAC2 and found that H2AZK4/7AC and H3K27AC were upregulated, which partially released EGFR-vIII-mediated inhibition of USP11, negative regulator of cell cycle. In addition, we demonstrated in vitro and in vivo that FK228 induced G1/S transition arrest in GBM with EGFR-vIII mutation. FK228 could enhance anti-tumour activity by upregulating expression of the tumour suppressor USP11 in GBM cells. EGFR-vIII mutation downregulates H2AZK4/7AC and H3K27AC, inhibiting USP11 expression though the PI3K/AKT-HDAC1/2 axis. FK228 is an effective and promising treatment for GBM with EGFR-vIII mutation.

/pdf/egfr-viii-downregulated-h2azk4-7ac-though-the-pi3k-akt-hdac2-4grjmzhc67.pdf

EGFR-vIII downregulated H2AZK4/7AC though the PI3K/AKT-HDAC2 axis to regulate cell cycle progression

Adherent junction associated protein 1 (AJAP1), a typical molecule of adherent junctions, has been found to be a tumor suppressor in many cancer types. Aberrant activation of β-catenin has been demonstrated to be associated with malignant biological properties of tumors including breast cancer. This study aimed to investigate the function and mechanism of AJAP1-mediated β-catenin activity of breast cancer lines in vitro and in breast cancer patients. AJAP1 and β-catenin expressions in breast cancer tissues and cell lines were detected by immunohistochemistry, western blotting and qRT-PCR. The EGF/EGFR axis-mediated AJAP1 attenuated β-catenin nuclear location was measured by western blotting, immunofluorescence assay, co-immunoprecipitation, luciferase assay and ubiquitination assays. Furthermore, the function of AJAP1 and β-catenin regulated breast cancer progression was explored both in vivo and in vitro. It was found that AJAP1 had a high negative correlation with β-catenin nuclear expression and was a novel tumor suppressor in breast cancer. AJAP1 loss can mediate β-catenin accumulated in cytoplasm and then transferred it to the nucleus, activating β-catenin transcriptional activity and downstream genes. Additionally, β-catenin can reverse the invasion, proliferation ability and tumorigenicity of the depletion of AJAP1 caused both in vivo and in vitro. Besides, EGF/EGFR also involved in the process of AJAP1-depiction induced β-catenin transactivation to the nucleus. More importantly, EGFR depletion/AJAP1 knocked down promoted the progression of breast cancer by regulating the activity of β-catenin nuclear transactivation. This study demonstrated that AJAP1 acted as a putative tumor suppressor while β-catenin nuclear localization positively fed back on EGF/EGFR-attenuated AJAP1 expression in breast cancer, which might be beneficial to develop new therapeutic targets for decreasing nuclear β-catenin-mediated malignancy in breast cancer.

/pdf/b-catenin-nuclear-localization-positively-feeds-back-on-egf-d8sma00msb.pdf

β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer

EGFR/EGFRvIII remodels the cytoskeleton via epigenetic silencing of AJAP1 in glioma cells.

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EGFR/EGFRvIII remodels the cytoskeleton via epigenetic silencing of AJAP1 in glioma cells.