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Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I

Dass, Randall A.; Sarshad, Aishe A.; Carson, Brittany B.; Feenstra, Jennifer M.; Kaur, Amanpreet; Obrdlik, Ales; Parks, Matthew M.; Prakash, Varsha; Love, Damon K. and Pietras, Kristian LU , et al. (2016) In PLoS Genetics 12(8).
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... (More)

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.

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PLoS Genetics
volume
12
issue
8
publisher
Public Library of Science
external identifiers
  • scopus:84984914891
  • wos:000382394500023
ISSN
1553-7390
DOI
10.1371/journal.pgen.1006217
language
English
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yes
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81766afc-f10e-425a-9fa2-1e99def3fe9a
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2016-10-04 08:37:03
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2017-01-15 04:41:54
@article{81766afc-f10e-425a-9fa2-1e99def3fe9a,
  abstract     = {<p>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.</p>},
  articleno    = {e1006217},
  author       = {Dass, Randall A. and Sarshad, Aishe A. and Carson, Brittany B. and Feenstra, Jennifer M. and Kaur, Amanpreet and Obrdlik, Ales and Parks, Matthew M. and Prakash, Varsha and Love, Damon K. and Pietras, Kristian and Serra, Rosa and Blanchard, Scott C. and Percipalle, Piergiorgio and Brown, Anthony M C and Vincent, C. Theresa},
  issn         = {1553-7390},
  language     = {eng},
  month        = {08},
  number       = {8},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1006217},
  volume       = {12},
  year         = {2016},
}