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Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor

Lance R Thomas1, Clare M Adams2, Jing Wang3

  • 1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.

Proceedings of the National Academy of Sciences of the United States of America
|November 27, 2019
PubMed

Insights

Disrupting the MYC-WDR5 interaction, crucial for cancer cell growth, led to significant tumor regression in a preclinical model. This finding highlights MYC-WDR5 as a potential therapeutic target for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The oncoprotein transcription factor MYC is frequently overexpressed in cancers and drives malignant progression.
  • MYC is a validated anticancer target, but direct pharmacological inhibition has proven challenging.
  • MYC function relies on cofactors, presenting an opportunity for therapeutic intervention by disrupting these interactions.

Purpose of the Study:

  • To investigate whether disrupting the interaction between MYC and its cofactor WDR5 can serve as a viable anticancer strategy.
  • To understand the role of WDR5 in MYC-mediated gene regulation and cancer maintenance.

Main Methods:

  • Development of a Burkitt's lymphoma model allowing the use of MYC mutants defective in WDR5 binding or nuclear functions.
  • Utilizing this system to assess the impact of MYC-WDR5 interaction disruption on MYC's chromatin recruitment and gene expression.
  • Evaluating tumor regression in vivo following disruption of the MYC-WDR5 interaction.

Main Results:

  • WDR5 facilitates MYC recruitment to chromatin, regulating genes associated with biomass accumulation.
  • Disruption of the MYC-WDR5 interaction in established cancers resulted in rapid and complete tumor regression in vivo.
  • The study demonstrates a direct link between WDR5, MYC function, and tumor growth.

Conclusions:

  • The MYC-WDR5 interaction is essential for maintaining the malignant state driven by MYC.
  • Targeting the MYC-WDR5 interaction represents a promising therapeutic strategy for cancers dependent on MYC.
  • Further research into MYC-WDR5 inhibitors could lead to novel anticancer agents, provided a therapeutic window can be established.
Keywords:
MYCcancercancer therapychromatinlymphoma

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