Epigenetic Inactivation of KLF4 is Associated with Urothelial Cancer Progression and Early Recurrence

• Published in: The Journal of urology Vol. 191; no. 2; pp. 493 - 501
• Main Authors: Li, Heng, Wang, Ji, Xiao, Wei, Xia, Ding, Lang, Bin, Wang, Tao, Guo, Xiaolin, Hu, Zhiquan, Ye, Zhangqun, Xu, Hua
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.02.2014; Elsevier
• Subjects: Adult; Aged; Biological and medical sciences; carcinoma; Carcinoma, Transitional Cell - genetics; Cell Line, Tumor; Disease Progression; DNA Methylation; Down-Regulation; Female; Gene Silencing; genes; Humans; Immunohistochemistry; Kruppel-Like Transcription Factors - genetics; Lentivirus; Male; Medical sciences; Middle Aged; mortality; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Neoplasm Recurrence, Local - genetics; Nephrology. Urinary tract diseases; Pelvic Neoplasms - genetics; Pelvic Neoplasms - pathology; tumor suppressor; Tumors; Tumors of the urinary system; Ureteral Neoplasms - genetics; Ureteral Neoplasms - pathology; urinary bladder; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urinary tract. Prostate gland; Urology; urothelium; Urothelium - pathology; NMIBC; TURBT; genes; urinary bladder; 5-AZA-dc; tumor suppressor; nonmuscle invasive bladder cancer; KLF4; urothelium; EMT; epithelial-to-mesenchymal transition; Krüppel-like factor 4; 5-aza-2-deoxycytidine; transurethral resection of bladder tumor; carcinoma; recurrence-free survival; mortality; glyceraldehyde-3-phosphate dehydrogenase; GAPDH; PCR; polymerase chain reaction; RFS; Urothelial cancer; Nephrology; Relapse; Urinary system disease; Carcinoma; Mortality; Urinary tract disease; Malignant tumor; Inactivation; Epidemiology; Urology; Krppel-like factor 4; Urinary system; Urinary bladder; Tumor progression; Epigenetics; Genetics; Early; Cancer; Tumor suppressor gene; Urothelium
• ISSN: 0022-5347; 1527-3792; 1527-3792
• DOI: 10.1016/j.juro.2013.08.087

Purpose KLF4 is a transcription factor with divergent functions in different malignancies. We analyzed KLF4 expression and DNA methylation, and their clinical relevance and biological function in urothelial cancer. Materials and Methods Immunohistochemistry and Sequenom™ MassARRAY® were done to detect the expression and promoter methylation of KLF4 in urothelial cancer tissues. The association of the recurrence-free survival rate and decreased KLF4 or KLF4 methylation status was analyzed by the Kaplan-Meier method, Cox regression analysis and ROC assay. Lentivirus based KLF4 over expression and dsRNA mediated knockdown were used to detect KLF4 functions in urothelial cancer in vitro and in vivo. Results KLF4 was down-regulated in urothelial cancer due to promoter hypermethylation. Each correlated with recurrence-free survival in patients with nonmuscle invasive bladder cancer after transurethral resection of bladder cancer, which potentiates them as valuable predictive biomarkers for early recurrence. Moreover, in and ex vivo experiments showed that KLF4 suppressed urothelial cancer cell growth, migration and invasion inhibited the epithelial-to-mesenchymal transition. Conclusions KLF4 may function as a tumor suppressor gene in urothelial cancer since down-regulation of KLF4 by promoter hypermethylation would promote cancer progression. In addition, decreased expression of KLF4 or its promoter hypermethylation may have predictive value for early recurrence in patients with nonmuscle invasive bladder cancer.