title: KAI1 gene is engaged in NDRG1 gene-mediated metastasis suppression through the ATF3-NFkappaB complex in human prostate cancer.
abstract: NDRG1 and KAI1 belong to metastasis suppressor genes, which impede the dissemination of tumor cells from primary tumors to distant organs. Previously, we identified the metastasis promoting transcription factor, ATF3, as a downstream target of NDRG1. Further analysis revealed that the KAI1 promoter contained a consensus binding motif of ATF3, suggesting a possibility that NDRG1 suppresses metastasis through inhibition of ATF3 expression followed by activation of the KAI1 gene. In this report, we found that ectopic expression of NDRG1 was able to augment endogenous KAI1 gene expression in prostate cancer cell lines, whereas silencing NDRG1 was accompanied with significant decrease in KAI1 expression in vitro and in vivo. In addition, our results of ChIP analysis indicate that ATF3 indeed bound to the promoter of the KAI1 gene. Importantly, our promoter-based analysis revealed that ATF3 modulated KAI1 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NFκB). Moreover, loss of KAI1 expression significantly abrogated NDRG1-mediated metastatic suppression in vitro as well as in a spontaneous metastasis animal model, indicating that KA11 is a functional downstream target of the NDRG1 pathway. Our result of immunohistochemical analysis showed that loss of NDRG1 and KAI1 occurs in parallel as prostate cancer progresses. We also found that a combined expression status of these two genes serves as a strong independent prognostic marker to predict metastasis-free survival of prostate cancer patients. Taken together, our result revealed a novel regulatory network of two metastasis suppressor genes, NDRG1 and KAI1, which together concerted metastasis-suppressive activities through an intrinsic transcriptional cascade.
authors: Department of Medical Microbiology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626, USA.
authors: Wen
authors: W
authors: Liu
authors: Megumi
authors: M
authors: Iiizumi-Gairani
authors: Hiroshi
authors: H
authors: Okuda
authors: Aya
authors: A
authors: Kobayashi
authors: Misako
authors: M
authors: Watabe
authors: Sudha K
authors: SK
authors: Pai
authors: Puspa R
authors: PR
authors: Pandey
authors: Fei
authors: F
authors: Xing
authors: Koji
authors: K
authors: Fukuda
authors: Vishnu
authors: V
authors: Modur
authors: Shigeru
authors: S
authors: Hirota
authors: Kazuyuki
authors: K
authors: Suzuki
authors: Toshimi
authors: T
authors: Chiba
authors: Masaki
authors: M
authors: Endo
authors: Tamotsu
authors: T
authors: Sugai
authors: Kounosuke
authors: K
authors: Watabe
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051861:Kangai-1 Protein / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000235:genetics; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D051700:Activating Transcription Factor 3; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051861:Kangai-1 Protein; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C490449:ATF3 protein, human; C497108:Atf3 protein, rat; C497688:CD82 protein, human; C497690:Cd82 protein, rat