Methyltransferase G9a promotes cervical cancer angiogenesis and decreases patient survival

// Ruey-Jien Chen 1 , Chia-Tung Shun 2 , Men-Luh Yen 1 , Chia-Hung Chou 1 and Ming-Chieh Lin 2 1 Department of Obstetrics and Gynecology, National Taiwan University, Taipei 100, Taiwan 2 Department of Pathology, National Taiwan University, Taipei 100, Taiwan Correspondence to: Ruey-Jien Chen, email: rjchen@ntuh.gov.tw Keywords: G9a, angiogenesis, cancer cell proliferation, xenograft, patient survival Received: April 09, 2016 Accepted: May 12, 2017 Published: July 07, 2017 ABSTRACT Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16. Depressing G9a by either pharmacological inhibitor or gene knock down significantly reduces angiogenic factor expression. Moreover, promoting G9a gene expression augments transcription and angiogenic function. A luciferase reporter assay suggests that knockdown of G9a inhibits transcriptional activation of interleukin-8. G9a depletion suppresses xenograft tumor growth in mouse model, which is linked to a decrease in microvessel density and proliferating cell nuclear antigen expression. Clinically, higher G9a expression correlates with poorer survival for cancer patients. For patients’ primary tumors a positive correlation between G9a expression and microvessel density also exists. In addition to increasing tumor cell proliferation, G9a promotes tumor angiogenesis and reduces the patient survival rate. G9a may possess great value for targeted therapies.