Different expression patterns and functions of acetylated and unacetylated Klf5 in the proliferation and differentiation of prostatic epithelial cells.
Different expression patterns and functions of acetylated and unacetylated Klf5 in the proliferation and differentiation of prostatic epithelial cells.
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DOI：
10.1371/journal.pone.0065538
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dong JT
中科院分区：
文献类型：
--
作者：
Xing C;Fu X;Sun X;Guo P;Li M;Dong JT
KLF5是调控多种生物过程的基本转录因子。虽然KLF5在前列腺癌中被认为是一种推定的肿瘤抑制因子，可能是由于其作为TGF-β抑制细胞增殖的效应物的功能，但在没有TGF-β的情况下，KLF5是未乙酰化的，可以促进细胞增殖。在这项研究中，我们利用小鼠前列腺和人前列腺上皮细胞的三维培养，评估了KLF5在前列腺上皮稳态和肿瘤发生中的表达和功能。组织学和分子分析表明，未乙酰化的klf5在基底细胞或未分化细胞中表达，而乙酰化的klf5主要在管腔细胞和/或分化细胞中表达。阉割导致的雄激素消耗增加了Klf5表达水平和剩余前列腺中Klf5阳性细胞的数量。在功能上，在人RWPE-1前列腺细胞系中敲低KLF5可减少三维培养中形成的球体数量。此外，敲除前列腺上皮细胞中的Klf5，通过前盆腔启动子驱动的Cre表达介导，当敲除一个Klf5等位基因时，不会引起肿瘤，但会促进细胞增殖并诱导增生。然而，敲除这两个Klf5等位基因会导致上皮细胞凋亡而不是细胞增殖。在被阉割的小鼠中，敲除Klf5导致更严重的前列腺萎缩。这些结果表明，KLF5在前列腺上皮细胞的增殖和分化中发挥作用，但单独缺失KLF5不足以诱导上皮细胞的恶性转化。
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.
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