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Tytuł:
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WT1 regulates HOXB9 gene expression in a bidirectional way.
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Autorzy:
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Schmidt V; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, 10117 Berlin, Germany.
Sieckmann T; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, 10117 Berlin, Germany.
Kirschner KM; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, 10117 Berlin, Germany.
Scholz H; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: .
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Źródło:
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Biochimica et biophysica acta. Gene regulatory mechanisms [Biochim Biophys Acta Gene Regul Mech] 2021 Nov-Dec; Vol. 1864 (11-12), pp. 194764. Date of Electronic Publication: 2021 Sep 08.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Amsterdam : Elsevier,
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MeSH Terms:
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Gene Expression Regulation, Developmental*
Homeodomain Proteins/*genetics
WT1 Proteins/*metabolism
Animals ; Cell Line, Tumor ; Embryo, Mammalian ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Kidney/embryology ; Kidney/pathology ; Kidney Neoplasms/genetics ; Kidney Neoplasms/pathology ; Mice ; Organ Culture Techniques ; Promoter Regions, Genetic ; Transcriptional Activation ; WT1 Proteins/genetics ; Wilms Tumor/genetics ; Wilms Tumor/pathology
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Contributed Indexing:
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Keywords: Gene expression; Homeobox gene family; Kidney development; Nephroblastoma; Transcription factor; Tumor suppressor
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Substance Nomenclature:
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0 (HOXB9 protein, human)
0 (Homeodomain Proteins)
0 (Hoxb9 protein, mouse)
0 (WT1 Proteins)
0 (WT1 protein, human)
0 (WT1 protein, mouse)
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Entry Date(s):
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Date Created: 20210911 Date Completed: 20211230 Latest Revision: 20211230
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Update Code:
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20240105
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DOI:
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10.1016/j.bbagrm.2021.194764
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PMID:
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34508900
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The homeoboxB9 (HOXB9) gene is necessary for specification of the anterior-posterior body axis during embryonic development and expressed in various types of cancer. Here we show that the Wilms tumor transcription factor WT1 regulates the HOXB9 gene in a bidirectional manner. Silencing of WT1 activates HOXB9 in Wt1 expressing renal cell adenocarcinoma-derived 786-0 cells, mesonephric M15 cells and ex vivo cultured murine embryonic kidneys. In contrast, HOXB9 expression in U2OS osteosarcoma and human embryonic kidney (HEK) 293 cells, which lack endogenous WT1, is enhanced by overexpression of WT1. Consistently, Hoxb9 promoter activity is stimulated by WT1 in transiently transfected U2OS and HEK293 cells, but inhibited in M15 cells with CRISPR/Cas9-mediated Wt1 deletion. Electrophoretic mobility shift assay and chromatin immunoprecipitation demonstrate binding of WT1 to the HOXB9 promoter in WT1-overexpressing U2OS cells and M15 cells. BASP1, a transcriptional co-repressor of WT1, is associated with the HOXB9 promoter in the chromatin of these cell lines. Co-transfection of U2OS and HEK293 cells with BASP1 plus WT1 prevents the stimulatory effect of WT1 on the HOXB9 promoter. Our findings identify HOXB9 as a novel downstream target gene of WT1. Depending on the endogenous expression of WT1, forced changes in WT1 can either stimulate or repress HOXB9, and the inhibitory effect of WT1 on transcription of HOXB9 involves BASP1. Consistent with inhibition of Hoxb9 expression by WT1, both transcripts are distributed in an almost non-overlapping pattern in embryonic mouse kidneys. Regulation of HOXB9 expression by WT1 might become relevant during kidney development and cancer progression.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
