Nuclear Dishevelled targets gene regulatory regions and promotes tumor growth

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Biology

Background:

• Dishevelled (DVL) is crucial for Wnt signaling, implicated in various diseases.
• The specific cellular functions and nuclear roles of DVL, particularly in breast cancer, are not well understood.
• Constitutive Wnt pathway activation is linked to breast cancer malignancy, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the nuclear functions of Dishevelled 3 (DVL3) in breast cancer.
• To identify novel DVL3 target genes and understand its regulatory mechanisms.
• To elucidate the role of nuclear DVL3 in mediating aberrant Wnt signaling and its impact on tumor growth.

Main Methods:

• Performed DVL3 Chromatin Immunoprecipitation sequencing (ChIP-seq) to identify DVL3-bound genomic regions.
• Utilized DVL3 depletion experiments to assess its impact on gene expression and epigenetic modifications.
• Employed in vivo breast cancer models to evaluate the effect of DVL3 inhibition on tumor growth.

Main Results:

• Identified novel target genes directly bound by DVL3.
• Demonstrated that DVL3 depletion alters KMT2D binding, epigenetic marks, and mRNA levels of target genes.
• Showed that DVL3 inhibition significantly reduces tumor growth in two distinct breast cancer models.

Conclusions:

• Uncovered novel functions of nuclear DVL3 in regulating genes involved in development, metabolism, chromatin remodeling, and tumorigenesis.
• Provided unique insights into how nuclear DVL3 mediates aberrant Wnt signaling in breast cancer.
• Established DVL3 as a potential therapeutic target for breast cancer treatment.