Interruption Of KLF5Acetylation Converts Its Function From Tumor Suppressor To Tumor Promoter In Prostate Cancer

Prostate cancer is the most common malignant of male urinary system and prone to invasion and migration. The incidences of prostate cancer are different in different countries and regions. In the developed countries, such as the countries in Europe and North America, one of the main causes of death is prostate caner because the disease incidence is so high. In China, the incidence and mortality of prostate cancer are lower than developed countries, but in recent years, the incidence of prostate cancer in China has increased because of the aging of population and the change of the eating habit. In order to improve the efficiency of prostate cancer treatment and the quality of life of the patients, plenty of prostate relative genes and the molecular mechanisms need to be studied.As a basic transcriptional factor, KLF5possesses both tumor suppressing function and tumor promoting function, although the mechanism controlling these opposing functions is unknown. In our previous studies, we have reported that KLF5promotes cell proliferation without TGF-β but inhibits cell proliferation with TGF-β in non-cancerous cells. TGF-β can recruit p300and induce the acetylation of KLF5, which sequentially alters the KLF5transcriptional complex and the expression of downstream genes such as MYC and p15, so KLF5converts from pro-proliferation to anti proliferation activity upon TGF-β-induced acetylation.In this paper, we tested whether the acetylation status of KLF5aslo determines its opposing functions in tumorigenesis of prostate cancer. First of all, we used prostate cancer cell lines DU145and PC-3as cell model. Cell proliferation of these two cell lines can be inhibited by TGF-β and they both express lower level of KLF5. We used both of these two cell line to establish stable clones expressing wild type KLF5and the K369R mutant which can abolish the acetylation of KLF5constitutively. The expression of wild type KLF5significantly inhibited cell proliferation, the K369R mutant lost this inhibitory function. KLF5downregulated MYC but upregulated p15, while the K369R mutant upregulated MYC and had no effect on p15expression. These results suggest that the suppressive function of KLF5 dependent on its acetylation.Second, we performed in vivo tumorigenesis assay by using nude mice and stable clones as mentioned above. KLF5also suppressed tumor growth in an acetylation-dependent manner, interestingly, deacetylation converted KLF5from a tumor-suppressive to tumor-promoting function. Blocking TGF-β signaling attenuated the tumor suppressor activity of KLF5.Finally, we sent the xenograft samples expressing the control vector pLHCX, wild type KLF5and the K369R mutant for RNA-Seq. The results from RNA-Seq suggest that AcKLF5and unAcKLF5are involved in different signaling pathways by regulating different downstream genes, which determines their different functions in tumorigenesis.In summary, AcKLF5can inhibit prostate cancer cell proliferation and tumor growth by regulating downstream genes such as MYC and p15. Abolishing acetylation converts the tumor suppressor function KLF5to tumor promoting. These results provide a novel mechanism that controls how KLF5can be both pro-and anti-tumorigenic. They also suggest that AcKLF5and unAcKLF5can respectively mediate the tumor suppressing and tumor promoting functions of TGF-β.