title: Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I.
abstract: Ribosome biogenesis is essential for cell growth and proliferation and is commonly elevated in cancer. Accordingly, numerous oncogene and tumor suppressor signaling pathways target rRNA synthesis. In breast cancer, non-canonical Wnt signaling by Wnt5a has been reported to antagonize tumor growth. Here, we show that Wnt5a rapidly represses rDNA gene transcription in breast cancer cells and generates a chromatin state with reduced transcription of rDNA by RNA polymerase I (Pol I). These effects were specifically dependent on Dishevelled1 (DVL1), which accumulates in nucleolar organizer regions (NORs) and binds to rDNA regions of the chromosome. Upon DVL1 binding, the Pol I transcription activator and deacetylase Sirtuin 7 (SIRT7) releases from rDNA loci, concomitant with disassembly of Pol I transcription machinery at the rDNA promoter. These findings reveal that Wnt5a signals through DVL1 to suppress rRNA transcription. This provides a novel mechanism for how Wnt5a exerts tumor suppressive effects and why disruption of Wnt5a signaling enhances mammary tumor growth in vivo.
authors: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America.
authors: Randall A
authors: RA
authors: Dass
authors: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.|Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors: Aishe A
authors: AA
authors: Sarshad
authors: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: Brittany B
authors: 0000-0002-1370-8935
authors: BB
authors: Carson
authors: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: Jennifer M
authors: JM
authors: Feenstra
authors: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, United States of America.
authors: Amanpreet
authors: A
authors: Kaur
authors: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.|Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors: Ales
authors: 0000-0001-8499-3879
authors: A
authors: Obrdlik
authors: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America.
authors: Matthew M
authors: 0000-0003-4283-9675
authors: MM
authors: Parks
authors: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: Varsha
authors: 0000-0003-3583-6468
authors: V
authors: Prakash
authors: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, United States of America.
authors: Damon K
authors: 0000-0002-3664-6968
authors: DK
authors: Love
authors: Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Lund, Sweden.
authors: Kristian
authors: K
authors: Pietras
authors: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Rosa
authors: R
authors: Serra
authors: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America.|Tri-Institutional PhD program in Chemical Biology, Weill Cornell Medical College, New York, New York, United States of America.
authors: Scott C
authors: SC
authors: Blanchard
authors: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.|Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors: Piergiorgio
authors: P
authors: Percipalle
authors: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, United States of America.
authors: Anthony M C
authors: AM
authors: Brown
authors: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, United States of America.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America.|Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: C Theresa
authors: CT
authors: Vincent
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D000072261:Dishevelled Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009697:Nucleolus Organizer Region / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012318:RNA Polymerase I / Q000235:genetics*; D012335:RNA, Ribosomal / Q000235:genetics; D037761:Sirtuins / Q000235:genetics; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics; D000071818:Wnt-5a Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D004275:DNA, Ribosomal; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D012335:RNA, Ribosomal; C510661:SIRT7 protein, human; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D012318:RNA Polymerase I; D037761:Sirtuins