Abstract 60: KLF5 deletion promotes but does not initiate prostate carcinogenesis

Abstract

Abstract KLF5 (Kruppel-like factor 5) is a basic transcription factor that is abundant in proliferating epithelial cells. Its locus at 13q21 is frequently deleted in human prostate cancer, suggesting a tumor suppressor function. Our previous study showed that TGF-beta, which is a differentiation signal for normal proliferating progenitor cells, acetylates KLF5 to reverse its function. Unacetylated KLF5 (unAc-KLF5) is pro-proliferative but acetylated KLF5 (Ac-KLF5) works with TGF-β to inhibit cell proliferation. Here we generated a Klf5-floxed mouse strain in which exons 2 and 3 of Klf5 are flanked by loxP sequences. By crossing Klf5-floxed mice with PB-Cre4 transgenic mice, we were able to delete the Klf5 gene specifically in prostatic epithelial cells. Because knockout of both Pten alleles induces prostate carcinoma, we also crossed Klf5-floxed mice with Pten-floxed mice to investigate Klf5 function in tumor progression. At different time points, prostates were collected and histological and molecular analyses were performed. We found that knockout of one Klf5 allele mainly increased cell proliferation and caused epithelial hyperplasia but was insufficient to initiate prostatic intraepithelial neoplasia (PIN). On the other hand, knockout of both Klf5 alleles mainly induced apoptosis in prostate epithelia. When combined with Pten knockout, the apoptosis was prevented due to the activation of PI3K survival signaling, making Klf5 null cells survive. With the deletion of one Pten allele, Klf5 deletion significantly increased cell proliferation and promoted the development of hyperplasia and PIN. When both Pten alleles were deleted, Klf5 deletion significantly enhanced tumor development, as indicated by increased tumor size and elimination of luminal structures. Immunohistochemical staining proved that cell cycle regulator p15 was downregulated in Klf5 knockout mice. Deletion of Klf5 also significantly induced phosphorylation of Erk1/2 MAPK and further increased Akt activity. In normal prostates, total Klf5 was detected in both luminal and basal cells of the prostate, while unAc-Klf5 and Ac-Klf5 were detected in basal and luminal cells respectively. In addition, oncogenic signals, such as Pten knockout, reduced Ac-Klf5 in differentiated luminal cells. In conclusion, deletion of Klf5 promotes cell proliferation and makes cells susceptible to other factor-induced carcinogenesis in the prostate, probably because of impaired proliferation-inhibitory function of Ac-Klf5. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 60. doi:1538-7445.AM2012-60