SnoN oncoprotein enhances estrogen receptor-α transcriptional activity.
Estrogen receptor-α (ERα) and transforming growth factor-beta (TGF-β) signaling pathways are essential regulators during mammary gland development and tumorigenesis. Ski-related novel gene (SnoN) is an oncoprotein and a negative feedback inhibitor of TGF-β signaling. We have previously reported that low expression of SnoN in ERα positive breast carcinomas is associated with favorable prognosis (Zhang et al. Cancer Res. (2003) 63, 5005-5010). Here we have studied the mechanism of a possible cross-talk between ERα and SnoN. We find that SnoN interacts with the estrogen-activated form of ERα in the nucleus. SnoN contains two highly conserved nuclear receptor binding LxxLL-like motifs and we show that mutations in these motifs reduce the interaction of SnoN with ERα. Over-expression of SnoN enhanced the transcriptional activity of ERα in estrogen response element (ERE)-reporter assays, augmented the expression of several ERα target genes and increased the proliferation of MCF7 breast carcinoma cells in an estrogen-dependent manner. Chromatin immunoprecipitation demonstrated that SnoN interacts with ERα at the TTF1 (pS2) gene promoter. Conversely, silencing of SnoN reduced both ERE-reporter activity and the expression of ERα target genes in MCF7 and T-47D breast cancer cells. Histone deacetylase inhibition increased the level of SnoN and SnoN-dependent enhancement of ERα-dependent transcription and SnoN supported the recruitment of p300 histone acetylase to ERα. This study reveals a novel mechanism that interconnects ERα and TGF-β signaling pathways by SnoN. Accordingly, the results indicate that high SnoN level promotes ERα signaling and possibly breast cancer progression.
Molecular Cancer Biology Program, Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland.
Arja M
AM
Band
Marikki
M
Laiho
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008156:Luciferases / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C060615:SKIL protein, human; D008156:Luciferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases