Interruption of KLF5 acetylation converts its function from tumor suppressor to tumor promoter in prostate cancer cells

KLF5 possesses both tumor suppressing and tumor promoting activities, though the mechanism controlling these opposing functions is unknown. In cultured noncancerous epithelial cells, KLF5 converts from proproliferative to antiproliferative activity upon TGF-induced acetylation, which sequentially alters the KLF5 transcriptional complex and the expression of genes such as p15 and MYC. In this study, we tested whether the acetylation status of KLF5 also determines its opposing functions in tumorigenesis using the PC-3 and DU 145 prostate cancer cell lines, whose proliferation is inhibited by TGF. KLF5 inhibited the proliferation of these cancer cells, and the inhibition was dependent on KLF5 acetylation. MYC and p15 showed the same patterns of expression change found in noncancerous cells. In nude mice, KLF5 also suppressed tumor growth in an acetylation-dependent manner. Furthermore, deacetylation switched KLF5 to tumor promoting activity, and blocking TGF signaling attenuated the tumor suppressor activity of KLF5. RNA sequencing and comprehensive data analysis suggest that multiple molecules, including RELA, p53, CREB1, MYC, JUN, ER, AR and SP1, mediate the opposing functions of AcKLF5 and unAcKLF5. These results provide novel insights into the mechanism by which KLF5 switches from antitumorigenic to protumorigenic function and also suggest the roles of AcKLF5 and unAcKLF5, respectively, in the tumor suppressing and tumor promoting functions of TGF. What's New? The highly expressed epithelial cell transcription factor KLF5 both suppresses and promotes tumor formation, though the mechanism behind its functional switching is unknown. Here, acetylation was found to be essential for KLF5 tumor suppression, whereas deacetylation switched KLF5 to tumor-promoting activity. KLF5's tumor suppressor activity was attenuated with inhibition of TGF signaling. In addition, target genes of KLF5 and TGF showed KLF5 acetylation-responsive expression patterns, and eight molecules were identified as possible mediators of KLF5's functional reverse. The study provides a novel mechanism for KLF5 functional switching in tumorigenesis and implicates unacetylated KLF5 in TGF tumor promotion.