Different Expression Patterns and Functions of Acetylated and Unacetylated Klf5 in the Proliferation and Differentiation of Prostatic Epithelial Cells

Changsheng Xing,Jin-Tang Dong,Xiaoying Fu,Xiaodong Sun,Peng Guo,Mei Li,Zhongjun Zhou

doi:10.1371/journal.pone.0065538

Abstract

KLF5 is a basic transcription factor that regulates multiple biological processes. While it was identified as a putative tumor suppressor in prostate cancer, likely due to its function as an effector of TGF-β in the inhibition of cell proliferation, KLF5 is unacetylated and promotes cell proliferation in the absence of TGF-β. In this study, we evaluated the expression and function of KLF5 in prostatic epithelial homeostasis and tumorigenesis using mouse prostates and human prostate epithelial cells in 3-D culture. Histological and molecular analyses demonstrated that unacetylated-Klf5 was expressed in basal or undifferentiated cells, whereas acetylated-Klf5 was expressed primarily in luminal and/or differentiated cells. Androgen depletion via castration increased both the level of Klf5 expression and the number of Klf5-positive cells in the remaining prostate. Functionally, knockdown of KLF5 in the human RWPE-1 prostate cell line decreased the number of spheres formed in 3-D culture. In addition, knockout of Klf5 in prostate epithelial cells, mediated by probasin promoter-driven Cre expression, did not cause neoplasia but promoted cell proliferation and induced hyperplasia when one Klf5 allele was knocked out. Knockout of both Klf5 alleles however, caused apoptosis rather than cell proliferation in the epithelium. In castrated mice, knockout of Klf5 resulted in more severe shrinkage of the prostate. These results suggest that KLF5 plays a role in the proliferation and differentiation of prostatic epithelial cells, yet loss of KLF5 alone is insufficient to induce malignant transformation in epithelial cells.

Highlights

Kruppel-like factor 5 (KLF5, known as BTEB2 or IKLF) is a basic transcription factor that is widely expressed in different types of tissues [1,2]
Stronger staining was detected in 100% of basal cells, whereas the staining was not as strong in luminal cells and only half of the luminal cells were positive for Klf5 (Fig. 1)
This observation is consistent with the recognition that KLF5 expression is usually higher in basal cells or undifferentiated cells and lower in luminal cells or differentiated cells in other tissues

Summary

Introduction

Kruppel-like factor 5 (KLF5, known as BTEB2 or IKLF) is a basic transcription factor that is widely expressed in different types of tissues [1,2]. It belongs to the KLF family, which is structurally characterized by three zinc-finger domains at the Cterminus [2,3,4]. KLF5 is typically pro-proliferative in non-transformed epithelial cells, which are most likely equivalent to progenitor cells. The bifunctional effects of KLF5 on cell proliferation could be due to post-translational modification under different cell contexts, as the pro-proliferative KLF5 becomes acetylated to inhibit cell proliferation upon the activation of TGF-b signaling, and interruption of its acetylation prevents its functional reversal in the proliferation of epithelial cells [13,14]

Methods

Results

Conclusion