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.
Highlights
Cancer’s biological capabilities are often listed as including unlimited cell proliferation [1], angiogenesis [2], telomere shortening [3], suppression of apoptosis [4], and invasion and metastasis [5]
We examined G9A expression in sections from normal and diseased uterine cervices using immunohistochemical staining
G9A expression was detected in the nuclei of carcinoma cells (Figure 1A)
Summary
Cancer’s biological capabilities are often listed as including unlimited cell proliferation [1], angiogenesis [2], telomere shortening [3], suppression of apoptosis [4], and invasion and metastasis [5]. Underlying these factors is genomic instability [6, 7]. DNA methylation with histone modification is a common hallmark of cancer cells [10, 11]. A DNA methylation signature may identify cancer patients who might benefit from a more aggressive treatment [13]
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