Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation.
Colon cancer is the second leading cause of cancer death in the United States. Krüppel-like factor 4 (KLF4) is a transcription factor involved in both proliferation and differentiation in the colon. It is down-regulated in both mouse and human colonic adenomas and has been implicated as a tumor suppressor in the gut, whereas in breast cancer, KLF4 is an oncogene. KLF4 is also involved in reprogramming differentiated cells into pluripotent stem cells. KLF4 can act as a transcriptional activator or repressor, but the underlying mechanisms are poorly understood. We found that p300, a CREB-binding protein-related protein, interacts with KLF4 both in vitro and in vivo and activates transcription. We further made the novel observation that endogenous KLF4 is acetylated by p300/CBP in vivo and that mutations of the acetylated lysines resulted in a decreased ability of KLF4 to activate target genes, suggesting that acetylation is important for KLF4-mediated transactivation. Furthermore, we found that KLF4 differentially modulates histone H4 acetylation at the promoters of target genes. Co-transfection of KLF4 and HDAC3 resulted in a synergistic repression of a cyclin B(1) reporter construct. Our results suggest that KLF4 might function as an activator or repressor of transcription depending on whether it interacts with co-activators such as p300 and CREB-binding protein or co-repressors such as HDAC3.
Evans
Paul M
PM
Department of Biochemistry and Molecular Biology, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
Zhang
Wen
W
Chen
Xi
X
Yang
Jun
J
Bhakat
Kishor K
KK
Liu
Chunming
C
D000107:Acetylation; D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D050882:CREB-Binding Protein; D019926:Cyclin B; D056744:Cyclin B1; D006655:Histone Deacetylases; D006657:Histones; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000099186:Histone Deacetylase 3; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse