Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis

Amy S Farrell1, Carl Pelz, Xiaoyan Wang

  • 1Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.

Insights

Pin1 enhances the DNA binding of Myc, a key cancer oncoprotein, promoting cell growth and proliferation. This interaction is crucial in cancer, particularly in aggressive breast cancer subtypes.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • The Myc oncoprotein is a master regulator of gene transcription, influencing a vast number of genes.
  • Mechanisms governing Myc's DNA recruitment and target gene specificity remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of Pin1 prolyl isomerase in regulating Myc's transcriptional activity and oncogenic function.
  • To investigate the interplay between Pin1 and Myc in gene regulation and cancer progression.

Main Methods:

  • Investigated the effect of Pin1 on serine 62-phosphorylated Myc recruitment to DNA.
  • Analyzed Myc's gene activation, degradation, and association with coactivators.
  • Examined Pin1 and Myc co-expression in cancer cell lines and patient data, including breast cancer subtypes.

Main Results:

  • Pin1 enhances the recruitment of phosphorylated Myc and coactivators to specific gene promoters, facilitating gene activation.
  • Pin1 promotes Myc release from DNA, which is linked to Myc degradation and regulation of cell growth and metabolism.
  • In cancer cells with defective Myc degradation, Pin1 still boosts Myc DNA binding but not degradation, leading to cooverexpression and a poor-outcome gene expression pattern in breast cancer.

Conclusions:

  • Pin1 plays a novel role in regulating transcription factors, specifically enhancing Myc's DNA binding and oncogenic activity.
  • The Pin1-Myc interaction contributes to oncogenic cooperation and drives a gene expression profile associated with poor prognosis in certain breast cancers.
  • Understanding this mechanism offers new insights into Myc regulation and potential therapeutic strategies targeting Pin1 and Myc in cancer.

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