Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes.
Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence, and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of beta-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of beta-catenin-reptin requires both increased beta-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of beta-catenin-reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-kappaB target genes.
Kim
Jung Hwa
JH
Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, South Korea.
Kim
Bogyou
B
Cai
Ling
L
Choi
Hee June
HJ
Ohgi
Kenneth A
KA
Tran
Chris
C
Chen
Charlie
C
Chung
Chin Ha
CH
Huber
Otmar
O
Rose
David W
DW
Sawyers
Charles L
CL
Rosenfeld
Michael G
MG
Baek
Sung Hee
SH
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D003094:Collagen; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D051548:Histone Acetyltransferases; D006801:Humans; D051861:Kangai-1 Protein; D007797:Laminin; D000074443:Lysine Acetyltransferase 5; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D051176:beta Catenin
D015703:Antigens, CD; C497688:CD82 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C497689:Cd82 antigen, mouse; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D051861:Kangai-1 Protein; D007797:Laminin; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D051176:beta Catenin; C059485:matrigel; D003094:Collagen; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5