Angiogenin contributes to bladder cancer tumorigenesis by DNMT3b-mediated MMP2 activation.
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.
University of Hawaii Cancer Center, Clinical & Translational Research Program, Honolulu, HI, USA.
Rafael
R
Peres
University of Hawaii Cancer Center, Clinical & Translational Research Program, Honolulu, HI, USA.
Hideki
H
Furuya
University of Hawaii Cancer Center, Cancer Prevention and Control Program, Honolulu, HI, USA.
Ian
I
Pagano
University of Hawaii Cancer Center, Clinical & Translational Research Program, Honolulu, HI, USA.|Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA.
Yoshiko
Y
Shimizu
University of Hawaii Cancer Center, Clinical & Translational Research Program, Honolulu, HI, USA.|Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA.
Kanani
K
Hokutan
University of Hawaii Cancer Center, Clinical & Translational Research Program, Honolulu, HI, USA.
Charles J
CJ
Rosser
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D018572:Disease-Free Survival; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D053208:Kaplan-Meier Estimate; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000097584:DNA Methyltransferase 3B
D014408:Biomarkers, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases; D020778:Matrix Metalloproteinase 2; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D012259:Ribonuclease, Pancreatic; D000097584:DNA Methyltransferase 3B; C046366:angiogenin; C522361:MMP2 protein, human
DNMT3b; MMP2; angiogenin; bladder cancer