title: Interruption of KLF5 acetylation converts its function from tumor suppressor to tumor promoter in prostate cancer cells.
abstract: 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 TGFβ-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 TGFβ. 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 TGFβ 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 TGFβ.
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Baotong
authors.initials: B
authors.lastname: Zhang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
authors.forename: Xinpei
authors.initials: X
authors.lastname: Ci
authors.forename: Ranran
authors.initials: R
authors.lastname: Zhao
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Siyuan
authors.initials: S
authors.lastname: Xia
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Gui
authors.initials: G
authors.lastname: Ma
authors.forename: Liya
authors.initials: L
authors.lastname: Fu
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D000107:Acetylation; D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011471:Prostatic Neoplasms / Q000209:etiology / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins
keywords: KLF5; TGFβ; acetylation; prostate cancer; tumorigenesis