Epigenetic inactivation of KLF4 is associated with urothelial cancer progression and early recurrence

Heng Li, Ji Wang, Wei Xiao, Ding Xia, Bin Lang, Tao Wang, Xiaolin Guo, Zhiquan Hu, Zhangqun Ye, Hua Xu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)493-501
Number of pages9
JournalJournal of Urology
Volume191
Issue number2
DOIs
StatePublished - Feb 2014

Bibliographical note

Funding Information:
The urological tumor tissue bank is sponsored by the Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Funding Information:
Supported by National Natural Science Foundation of China ( 31072238 , 31172441 , 81170650 and 81101944 ), and National Major Scientific and Technological Special Project for Significant New Drugs Development ( 2012ZX09303018 ).

Keywords

  • carcinoma
  • genes
  • mortality
  • tumor suppressor
  • urinary bladder
  • urothelium

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