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

Michael Rose¹, Claudia Schubert, Laura Dierichs

¹a Molecular Oncology Group; Institute of Pathology ; RWTH Aachen University ; Aachen , Germany.

|January 28, 2015

Abstract:

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.

Insights

CREB3L1 acts as a tumor suppressor in bladder cancer, with its expression reduced by promoter hypermethylation. Restoring CREB3L1 inhibits cancer cell migration and growth, suggesting its potential therapeutic role.

Area of Science:

Oncology
Molecular Biology
Cancer Genetics

Background:

CREB3L1 (CREB family basic leucine zipper transcription factor 3 like 1) is a recently identified metastasis suppressor in breast cancer.
Its role and regulation in bladder cancer remain largely unexplored.

Purpose of the Study:

To investigate the expression, regulation, and functional significance of CREB3L1 in bladder cancer.
To identify CREB3L1's potential role as a tumor suppressor in this malignancy.

Main Methods:

Analysis of CREB3L1 mRNA expression and promoter methylation in primary bladder tumors (n=64) and an independent dataset (n=184).
Immunohistochemical assessment of CREB3L1 protein levels in bladder cancer tissues.
In vitro functional assays using bladder cancer cell lines to evaluate the impact of CREB3L1 re-expression on cell migration and colony formation.
Identification of potential CREB3L1 target genes using molecular assays.

Main Results:

Significant downregulation of CREB3L1 mRNA expression in bladder cancer tissues, correlated with tumor-specific promoter hypermethylation.
Pyrosequencing indicated an association between CREB3L1 methylation and a more aggressive bladder cancer phenotype.
Reduced CREB3L1 protein expression observed in bladder tumors, particularly nuclear loss in aggressive cells.
Re-expression of CREB3L1 suppressed migration and colony growth in high-grade, invasive bladder cancer cells.
HTRA3, a TGF-β signaling inhibitor, identified as a putative target gene of CREB3L1.

Conclusions:

CREB3L1 is frequently downregulated in bladder cancer due to promoter hypermethylation, suggesting its role as a tumor suppressor.
CREB3L1 re-expression inhibits bladder cancer cell aggressiveness in vitro.
CREB3L1 may exert its tumor-suppressive function partly through regulating target genes like HTRA3.

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Keywords:

ATCC, American Type Culture Collection BMP-2, bone morphogenetic protein 2 CA, California 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)HTRA3 IQR, interquartile range IRS, immunoreactive score LMU, Ludwig-Maximilians-University M, methylated MIBC, muscle invasive bladder cancer MSP, methylation specific PCR NMIBC, non-muscle invasive bladder cancer NU, normal urothelium OASIS / CREB3L1 OASIS, old astrocyte specifically-induced substance PCR, polymerase chain reaction RIP, regulated intramembrane proteolysis RWTH, Rheinisch Westfälisch Technische Hochschule SP1, site 1 protease SP2, site 2 protease TCGA, The Cancer Genome Atlas TGF-β, 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 bladder cancer cDNA, copy number desoxyribonucleic acid mRNA, messenger ribo nucleic acid n, number ns, not significant pTa, papillary non-invasive tumors promoter methylation s.e.m., standard error of the margin tumor cell migration tumor suppressor gene

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