CINP is a novel cofactor of KLF5 required for its role in the promotion of cell proliferation, survival and tumor growth

• Type of Material: Article
• Authors: Qiao Wu, Nankai University; Changyin Fu, Nankai University; Menglin Li, Nankai University; Juan Li, Nankai University; Zhigui Li, Yale University; Leilei Qi, Nankai University; Xinpei Ci, Nankai University; Gui Ma, Nankai University; Ang Gao, Nankai University; Xing Fu, Nankai University; A Jun, Nankai University; An Na, Nankai University; Mingcheng Liu, Nankai University; Yixiang Li, Emory University; Jamie L. King, Emory University; Liya Fu, Nankai University; Baotong Zhang, Emory University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2019-02-01
• Publisher: Wiley Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 UICC
• Final Published Version (URL): http://dx.doi.org/10.1002/ijc.31908
• Title of Journal or Parent Work: International Journal of Cancer
• Volume: 144
• Issue: 3
• Start Page: 582
• End Page: 594
• Grant/Funding Information: This work was supported in part by grant 81130044 from the National Natural Science Foundation of China and grant R01CA171189 from the National Institutes of Health.
• Keywords: tumorigenesis; BOX; PHOSPHORYLATION; Science & Technology; TRANSCRIPTION FACTOR; ACTIVATION; BINDING-PROTEIN; KRUPPEL-LIKE FACTOR-5; CANCER; Kruppel-like factor 5; ACETYLATION; cyclin-dependent kinase 2-interacting protein; cell proliferation; cell survival; EXPRESSION; SUPPRESSES; Life Sciences & Biomedicine; Oncology
• Research Categories: Health Sciences, Oncology

Abstract

Krüppel-like factor 5 (KLF5) both suppresses and promotes tumor growth depending on cellular context. The mechanisms underlying tumor promotion could be targetable for therapy. Although a number of transcriptional targets of KLF5 have been identified and implicated in KLF5-mediated tumor growth, how KLF5 regulates these genes remains to be addressed. Here we performed coimmunoprecipitation (co-IP) and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the TSU-Pr1 bladder cancer cell line, in which KLF5 is shown to promote tumor growth, to identify KLF5-interacting nuclear proteins that are necessary for KLF5’s tumor promoting function. LC–MS/MS revealed 122 potential KLF5 binding proteins in the nuclear proteins precipitated by the KLF5 antibody, and the top nine candidates included AHNAK, TFAM, HSDL2, HNRNPC, CINP, IST1, FBL, PABPC1 and SNRNP40. SRB assays of these nine proteins indicated that silencing CINP had the most potent inhibitory effect on cell growth in KLF5-expressing cells but did not affect parental TSU-Pr1 cells. Further analyses not only confirmed the physical interaction between KLF5 and CINP, also demonstrated that knockdown of CINP attenuated the effects of KLF5 on cell cycle progression, apoptosis and tumorigenesis. Silencing CINP also attenuated the effect of KLF5 on the expression of a number of genes and signaling pathways, including cell cycle regulator Cyclin D1 and apoptosis-related Caspase 7. These results suggest that CINP is a cofactor of KLF5 that is crucial for the promotion of tumor growth, and that the KLF5-CINP interaction could be a novel therapeutic target for inhibiting KLF5-promoted tumor growth.