Activation of EZH2 and SUZ12 Regulated by E2F1 Predicts the Disease Progression and Aggressive Characteristics of Bladder Cancer.
OBJECTIVE
Previous study identified E2F1 as a key mediator of non-muscle-invasive bladder cancer (NMIBC) progression. The aim of this study was to identify the E2F1-related genes associated with poor prognosis and aggressive characteristics of bladder cancer.


METHODS
Microarray analysis was performed to find E2F1-related genes associated with tumor progression and aggressiveness in the gene expression data from 165 primary patients with bladder cancer. The biologic activity of E2F1-related genes in tumor progression and aggressiveness was confirmed with experimental assays using bladder cancer cells and tumor xenograft assay.


RESULTS
The expression of E2F1 was significantly associated with EZH2 and SUZ12. The overexpression of E2F1, EZH2, and SUZ12 enhanced cancer progression including cell colony formation, migration, and invasiveness. Knockdown of these genes reduced motility, blocked invasion, and decreased tumor size in vivo. E2F1 bound the proximal EZH2 and SUZ12 promoter to activate transcription, suggesting that E2F1 and its downstream effectors, EZH2 and SUZ12, could be important mediators for the cancer progression. In addition, we confirmed an association between these genes and aggressive characteristics. Interestingly, the treatment of anticancer drugs to the cells overexpressing E2F1, EZH2, and SUZ12 induced the expression of CD44, KLF4, OCT4, and ABCG2 known as cancer stem cell (CSC)-related genes.


CONCLUSIONS
The link between E2F1, EZH2, and/or SUZ12 revealed that E2f1 directly regulates transcription of the EZH2 and SUZ12 genes. The signature of E2F1-EZH2-SUZ12 shows a predictive value for prognosis in bladder tumors and the E2F1-EZH2-SUZ12-driven transcriptional events may regulate the cancer aggressiveness and chemo-resistance, which may provide opportunity for development of new treatment modalities.
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
Se-Ra
SR
Lee
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
Yun-Gil
YG
Roh
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Seon-Kyu
SK
Kim
Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
Ju-Seog
JS
Lee
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
So-Young
SY
Seol
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
Hyun-Hee
HH
Lee
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
Won-Tae
WT
Kim
Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Wun-Jae
WJ
Kim
Departments of Molecular Biology and Immunology, College of Medicine, Kosin University, Busan, Republic of Korea.
Jeonghoon
J
Heo
Departments of Parasitology and Genetics, Kosin University College of Medicine, Busan, Republic of Korea.
Hee-Jae
HJ
Cha
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
Tae-Hong
TH
Kang
Department of Biological Science, Dong-A University, Busan, Republic of Korea.
Jin Woong
JW
Chung
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. shleem@dau.ac.kr chu@kribb.re.kr.
In-Sun
IS
Chu
Department of Biological Science, Dong-A University, Busan, Republic of Korea. shleem@dau.ac.kr chu@kribb.re.kr.
Sun-Hee
SH
Leem
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011379:Prognosis; D018874:Spheroids, Cellular; D014157:Transcription Factors; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
D050687:E2F1 Transcription Factor; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2