US EPA

2994133 

Journal Article 

OASIS/CREB3L1 is epigenetically silenced in human bladder cancer facilitating tumor cell spreading and migration in vitro 

Rose, M; Schubert, C; Dierichs, L; Gaisa, NT; Heer, M; Heidenreich, A; Knuechel, R; Dahl, E 

2014 

Yes 

Epigenetics
ISSN: 1559-2294
EISSN: 1559-2308 

9 

12 

1626-1640 

English 

25625847 

10.4161/15592294.2014.988052 

WOS:000349364000008 

CREB3L1 has been recently proposed as a novel metastasis suppressor gene in breast cancer. Our current study highlights CREB3L1 expression, regulation, and function in bladder cancer. We demonstrate a significant downregulation of CREB3L1 mRNA expression (n = 64) in primary bladder cancer tissues caused by tumor-specific CREB3L1 promoter hypermethylation (n = 51). Based on pyrosequencing CREB3L1 methylation was shown to be potentially associated with a more aggressive phenotype of bladder cancer. These findings were verified by an independent public data set containing data from 184 bladder tumors. In addition, immunohistochemical evaluation showed that CREB3L1 protein expression is decreased in bladder cancer tissues as well. Interestingly, protein loss is predominately observed in the nuclei of aggressive tumor cells. Based on in vitro models we clearly show that CREB3L1 re-expression mediates suppression of tumor cell migration and colony growth of high grade and invasive bladder cancer cells. The candidate tumor suppressor and TGF-β signaling inhibitor HTRA3 was furthermore identified as putative target gene of CREB3L1 in both invasive J82 bladder cells and primary bladder tumors. Hence, our data provide for the first time evidence that the transcription factor CREB3L1 may have an important role as a putative tumor suppressor in bladder cancer. 

bladder cancer; HTRA3; OASIS; CREB3L1; promoter methylation; tumor cell migration; tumor suppressor gene; ATCC; American Type Culture Collection; BMP-2; bone morphogenetic protein 2; CA; California; cDNA; copy number desoxyribonucleic acid; CIS; Carcinoma in situ; CREB3L1; element binding protein 3-like 1; DAB; 3-3 diaminobenzidine; DAC; 5-aza-2-deoxycytidine; DNA; desoxyribonucleic acid; EK; ethics committee; ER; endoplasmic reticulum; FC; fold change; FFPE; formalin fixed paraffin embedded; G1; well differentiated; G2; moderately differentiated; G3; poorly differentiated; GAPDH; glyceraldehyde 3-phosphate dehydrogenase; HCV; Hepatitis C virus; HPV; human papilloma virus; HTRA (1-4); high-temperature requirement factor A (1-4); IQR; interquartile range; IRS; immunoreactive score; LMU; Ludwig-Maximilians-University; M; methylated; MIBC; muscle invasive bladder cancer; mRNA; messenger ribo nucleic acid; MSP; methylation specific PCR; n; number; NMIBC; non-muscle invasive bladder cancer; ns; not significant; NU; normal urothelium; OASIS; old astrocyte specifically-induced substance; PCR; polymerase chain reaction; pTa; papillary non-invasive tumors; RIP; regulated intramembrane proteolysis; RWTH; Rheinisch Westfalisch Technische Hochschule; s; e; m; standard error of the margin; SP1; site 1 protease; SP2; site 2 protease; TCGA; The Cancer Genome Atlas; TGF-; transforming growth factor beta; TSA; trichostatin A; TSS; transcription start site; U; unmethylated; UC; urothelial cell cancer; UPR; unfold protein response; USA; United States of America; WHO; World Health Organization; WI; Wisconsin