title: p21 and CK2 interaction-mediated HDAC2 phosphorylation modulates KLF4 acetylation to regulate bladder cancer cell proliferation.
abstract: Krüppel-like factor 4 (KLF4) is a transcription factor involved in both tumor suppression and oncogenesis as a transcriptional activator or repressor in a context-dependent manner. KLF4 acts as a regulator of p53 depending on p21 status in breast cancer. However, the mechanisms underlying the distinct role of KLF4 remain poorly understood. Here, we revealed that p21 depletion converted KLF4 from a cell cycle inhibitor to a promoter of bladder cancer cell proliferation. Additionally, KLF4 was acetylated in a p21-dependent manner to inhibit bladder cancer cell growth as a tumor suppressor. However, deacetylated KLF4 functioned as an oncogene promoting bladder cancer cell proliferation. Mechanistically, p21 and CK2 interaction, but not CK2 alone, enhanced HDAC2 phosphorylation and restricted KLF4 deacetylation and subsequent tumor promotion. Furthermore, we observed that KLF4 was acetylated by CBP/p300 and that overexpression of CBP resulted in KLF4 acetylation and tumor suppression even in p21-depleted bladder cancer cells. Moreover, we discovered that Notch-1 knockdown-induced KLF4 is acetylated form of KLF4, which may mediate Notch-1 function in bladder cancer cell proliferation. Our data demonstrate that KLF4 acts as a tumor suppressor or oncogene to activate or repress target gene transcription depending on its acetylation status, which is regulated by p21 and CK2 interaction-mediated HDAC2 phosphorylation. Targeting KLF4 at the post-transcriptional levels may provide novel insight for bladder cancer therapy.
authors.affiliation: Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Urology, Military General Hospital of Beijing PLA, Beijing, 100700, China.
authors.forename: Zhuo-Min
authors.initials: ZM
authors.lastname: Jia
authors.affiliation: Department of Urology, Military General Hospital of Beijing PLA, Beijing, 100700, China. aixing0007@163.com.
authors.forename: Xing
authors.initials: X
authors.lastname: Ai
authors.affiliation: Department of Urology, Military General Hospital of Beijing PLA, Beijing, 100700, China.
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Teng
authors.affiliation: Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Bao-Jun
authors.initials: BJ
authors.lastname: Wang
authors.affiliation: Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, 100853, China. zhangxu_2016@sina.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D047390:Casein Kinase II / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D047390:Casein Kinase II; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: CK2; HDAC2 phosphorylation; KLF4 acetylation; Notch-1; p21