Cbx7 is epigenetically silenced in glioblastoma and inhibits cell migration by targeting YAP/TAZ-dependent transcription.
Glioblastomas (GBM) are the most malignant form of astrocytomas which are difficult to treat and portend a grave clinical course and poor prognosis. In this study, we identified Chromobox homolog 7 (Cbx7), a member of Polycomb Repressive Complex 1 (PRC1), as a downregulated gene in GBM owing to its promoter hypermethylation. Bisulphite sequencing and methylation inhibitor treatment established the hypermethylation of Cbx7 in GBM. Exogenous overexpression of Cbx7 induced cell death, inhibited cell proliferation, colony formation and migration/invasion of the glioma cells. GSEA of Cbx7 regulated genes identified Cbx7 as a repressor of transcription co-activators YAP/TAZ, the inhibitory targets of the Hippo signalling pathway. In good correlation, the exogenous expression of Cbx7 repressed the YAP/TAZ-dependent transcription and downregulated CTGF, a bonafide YAP/TAZ target. We also observed reduced levels of phospho-JNK in Cbx7 expressing cells. Additionally, CTGF silencing and pharmacological inhibition of JNK also inhibited glioma cell migration. Further, Cbx7 failed to inhibit cell migration significantly in the presence of exogenously overexpressed CTGF or constitutively active JNK. Thus, our study identifies Cbx7 as an inhibitor of glioma cell migration through its inhibitory effect on YAP/TAZ-CTGF-JNK signalling axis and underscores the importance of epigenetic inactivation of Cbx7 in gliomagenesis.
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
Zahid
Z
Nawaz
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
Vikas
V
Patil
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
Anjali
A
Arora
Department of Neurosurgery, Sri Satya Sai Institute of Higher Medical Sciences, Bangalore 560066, India.
Alangar S
AS
Hegde
Departments of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
Arimappamagan
A
Arivazhagan
Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
Vani
V
Santosh
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
Kumaravel
K
Somasundaram
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics*; D000090683:Hippo Signaling Pathway; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C503627:CBX7 protein, human; C526317:CCN2 protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D063150:Polycomb Repressive Complex 1; D017346:Protein Serine-Threonine Kinases