Abstract
Epigenetic-mediated gene activation/silencing plays a crucial role in human tumorigenesis. Eliciting the underlying mechanism behind certain epigenetic changes is essential for understanding tumor biology. Previous studies in human cancers revealed an unrecognized interplay between Angiogenin (ANG) and matrix metalloproteinase-2 (MMP2) leading to pronounced tumorigenesis. Here we provide multiple lines of evidence further indicating ANG oncogenic potential. ANG expression resulted in the hypomethylated state of the MMP2 gene, which led to increased gene expression of MMP2. More than that, our global DNA methylation microarray analysis showed that gene manipulation of ANG affected a variety of pathways, such as cell migration, angiogenesis and specifically, tumor suppressor genes. Mechanistically, ANG negatively regulated DNA methyltransferase 3b (DNMT3b) enzymatic activity by down-regulating its expression and inhibiting its recruitment to the MMP2 promoter. Consistent with this, ANG-MMP2 overexpression and DNMT3b underexpression correlated with reduction in disease free survival of human bladder cancer patients. Together, the results continue to establish ANG as an oncoprotein and further reveal that ANG contributes to oncogenesis by the activation of MMP2 through modulation of DNMT3b functions.
Highlights
Changes in cancer cell transcriptome can be driven by genetic and epigenetic alterations
We demonstrate that ANG can positively regulate matrix metalloproteinase-2 (MMP2) expression
Expression of ANG, DNA methyltransferase 3b (DNMT3b) and MMP2 is correlated with disease free survival in human bladder cancer
Summary
Changes in cancer cell transcriptome can be driven by genetic and epigenetic alterations. DNA methylation controls these biologic processes by its ability to repress the gene transcription. DNMT3a and DNMT3b function as de novo methyltransferases to establish new methylation patterns by targeting normally unmethylated CpG sites on gene promoters [6]. We reported a novel interplay between angiogenin (ANG), a potent mediator of angiogenesis, and matrix metalloproteinase-2 (MMP2) in human bladder tumors [8]. We showed that forced ANG overexpression in benign human bladder UROtsa cell line induced cellular survival, proliferation, endothelial tube formation and xenograft angiogenesis and growth by mediating the MAPK/ERK-MMP2 axis [8]. When ANG, MMP2 are overexpressed and DNMT3b expression reduced in bladder tumors, there is a significant reduction in disease specific survival, attesting to ANG, DMT3b and MMP2 ability to further risk stratify patients that may require a more aggressive, even personalized, management plan. Our findings pave the way to advance our understanding of human bladder tumor biology and confirm ANG as a potential biomarker and as a target for therapeutic intervention
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