Nuclear Dishevelled targets gene regulatory regions and promotes tumor growth

Isabel Castro-Piedras, Monica Sharma, Jennifer Brelsfoard, David Vartak, Edgar G. Martinez, Cristian Rivera, Deborah Molehin, Robert K. Bright, Mohamed Fokar, Josee Guindon, Kevin Pruitt

Research output: Contribution to journalArticlepeer-review

Abstract

Dishevelled (DVL) critically regulates Wnt signaling and contributes to a wide spectrum of diseases and is important in normal and pathophysiological settings. However, how it mediates diverse cellular functions remains poorly understood. Recent discoveries have revealed that constitutive Wnt pathway activation contributes to breast cancer malignancy, but the mechanisms by which this occurs are unknown and very few studies have examined the nuclear role of DVL. Here, we have performed DVL3 ChIP-seq analyses and identify novel target genes bound by DVL3. We show that DVL3 depletion alters KMT2D binding to novel targets and changes their epigenetic marks and mRNA levels. We further demonstrate that DVL3 inhibition leads to decreased tumor growth in two different breast cancer models in vivo. Our data uncover new DVL3 functions through its regulation of multiple genes involved in developmental biology, antigen presentation, metabolism, chromatin remodeling, and tumorigenesis. Overall, our study provides unique insight into the function of nuclear DVL, which helps to define its role in mediating aberrant Wnt signaling.

Original languageEnglish
Article numbere50600
JournalEMBO Reports
Volume22
Issue number6
DOIs
StatePublished - Jun 4 2021

Keywords

  • ChIP-seq
  • DVL
  • Wnt
  • breast cancer
  • epigenetics

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