KLF4 and KLF5 regulate proliferation, Apoptosis and invasion in esophageal cancer cells

Abstract

ABBREVIATIONSECM extracellular matrix MTT 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide ACKNOWLEDGEMENTSWe would like to acknowledge support from the University of Pennsylvania Center for Molecular Studies in Digestive and Liver Disease (NIH NIDDK P30 DK050306) through the Morphology Core, the Molecular Biology Core, and the Transgenic and Chimeric Mouse Facility, and from the NIH NCI through PO1-CA098101 ("Mechanisms of Esophageal Carcinogenesis"). We thank Dr. Hiroshi Nakagawa for reagents and advice. J.P.K. was supported by K08 and R03 Awards from the NIH NIDDK, a Measey Foundation Fellowship, and a GlaxoSmithKline Institute for Digestive Health Basic Research Award. Research Paper KLF4 and KLF5 Regulate Proliferation, Apoptosis and Invasion in Esophageal Cancer Cells ABSTRACTKLF4 and KLF5, members of the KLF family of transcription factors, play key roles in proliferation, differentiation, and carcinogenesis in a number of gastrointestinal tissues. While KLF4 is expressed in differentiating epithelial cells, KLF5 is found in proliferating cells of the gastrointestinal tract, including the esophagus. KLF4 regulates a number of genes vital for esophageal epithelial differentiation, and decreased expression of KLF4 is seen in esophageal squamous cancers. Nonetheless, the roles of KLF4 and KLF5 in esophageal tumor progression are not known. Here, using TE2 cells stably infected with retroviral vectors to express KLF4 or KLF5, we demonstrate that KLF4 and KLF5 are key players in a number of cellular processes critical for esophageal carcinogenesis. TE2 cells, derived from a patient with poorly differentiated esophageal squamous cancer, normally lack KLF4 and KLF5. Expression of KLF5 in TE2 cells inhibits proliferation, and both KLF4 and KLF5 decrease viability after treatment with hydrogen peroxide and increase anoikis. In response to DNA damage from UV irradiation, viability is decreased in KLF5 but not KLF4 infected cells. Both KLF4 and KLF5 upregulate the cdk inhibitor p21 waf1/cip1 following UV irradiation, but the pro-apoptotic protein BAX is markedly induced only by KLF5. Thus KLF4 may preferentially activate DNA repair pathways while KLF5 induces both DNA repair and apoptosis after UV irradiation. Expression of KLF4 or KLF5 in TE2 cells also inhibits invasion, consistent with a role for each in preventing tumor metastasis. In summary, KLF4 and KLF5 regulate esophageal carcinogenesis by affecting proliferation, apoptosis, and invasion.

Krüppel-like factor 5 promotes breast cell proliferation partially through upregulating the transcription of fibroblast growth factor binding protein 1

“…KLF5 promotes breast cell proliferation KLF5 has been shown to promote cell proliferation in multiple cell lines (Yang et al, 2005;Chen et al, 2006). To test KLF5's role in breast cancer proliferation, we manipulated KLF5 protein levels in multiple breast cell lines and measured DNA synthesis.…”

Proteasomal degradation of the KLF5 transcription factor through a ubiquitin‐independent pathway

“…2C). Finally, WWP1 also efficiently targeted KLF5DN [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] for degradation like KLF5-FLAG (Fig. 2D).…”

“…KLF5 modulates multiple cellular processes, such as proliferation [6], differentiation [7,8], cell cycle [4], and apoptosis [9] through regulating expression of multiple important target genes including PDGFa [10], PPARc [8], NF-jB [11], and cyclinD1 [12,4].…”

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

“…Overexpression of KLF4 could be detected in oropharynx (26) and mammary carcinomas (27). Moreover, it has been reported to inhibit metastasis of several cancers, including esophageal (28), pancreatic (23), and colorectal cancer cells (29). In addition, KLF4 mRNA is targeted by miR-145 (30), implicating the post-transcriptional control of KLF4.…”