title: Sp1 is necessary for gene activation of Adamts17 by estrogen.
abstract: Adamts17 is a member of a family of secreted metalloproteinases. In this report, we show that knockdown of Adamts17 expression induces apoptosis and inhibits breast cancer cell growth. Adamts17 expression can rapidly be induced by estrogens. siRNA knockdown of Sp1 or Myc demonstrated that Sp1 is required to induce Adamts17 gene expression in response to estrogen. Moreover, reporter assays showed that the proximal promoter and the upstream sequences were not capable of conferring estrogen responsiveness, suggesting that Sp1 elements may be located in the downstream intronic region. We further demonstrated that Sp1 and Myc binding in the proximal promoter region contributed to the Adamts17 basal expression. Furthermore, histone deacetylase (HDAC) and methylase inhibitors also induced Adamts17 expression, indicating that epigenetic alterations, such as aberrant HDAC and/or methylation are associated with dysregulated Adamts17 expression. By meta-analysis using Oncomine microarray data, we found that higher Adamts17 expression is found in several human cancer cell subtypes, especially in breast ductal carcinoma. Moreover, we found that there is an inverse correlation between higher Adamts17 expression and patients' survival. Our study suggests that Adamts17 may support breast cancer cell growth and survival.
authors.affiliation: Clinic of Gynecological Endocrinology and Reproductive Medicine, University of Basel, Spitalstrasse 21, CH-4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland; Department of Gynecology and Obstetrics, Second Hospital of Jilin University, Changchun City, Jilin Province, P.R. China.
authors.forename: Zanhui
authors.initials: Z
authors.lastname: Jia
authors.forename: Shuping
authors.initials: S
authors.lastname: Gao
authors.forename: Nadira
authors.initials: N
authors.lastname: M'Rabet
authors.forename: Christian
authors.initials: C
authors.lastname: De Geyter
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000071096:ADAMTS Proteins; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D044584:Carcinoma, Ductal / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D004967:Estrogens; D056572:Histone Deacetylase Inhibitors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C579149:ADAMTS17 protein, human
keywords: APOPTOSIS; Adamts17; BREAST CANCER; GENE REGULATION; Sp1