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O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer

Yi Zhang1, Shuyan Zhou1, Yan Kai1

  • 1Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Nature Communications
|July 3, 2024
PubMed

Insights

Microphthalmia-associated transcription factor (MITF) activation via O-GlcNAcylation drives resistance to CDK4/6 inhibitors in breast cancer. Inhibiting MITF or O-GlcNAcylation re-sensitizes tumors to palbociclib, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial for cell cycle regulation and cancer progression.
  • CDK4/6 inhibitors (CDK4/6i) show efficacy in breast cancer treatment.
  • Acquired resistance to CDK4/6i, like palbociclib, presents a significant clinical challenge.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying palbociclib resistance in breast cancer.
  • To identify novel therapeutic targets for overcoming CDK4/6 inhibitor resistance.

Main Methods:

  • High-throughput combinatorial drug screening.
  • Genomic sequencing.
  • O-GlcNAcylation assays.
  • Cellular localization studies.
  • Analysis of clinical patient samples.

Main Results:

  • Microphthalmia-associated transcription factor (MITF) is activated by O-GlcNAcylation via O-GlcNAc transferase (OGT) in palbociclib-resistant cells and tumors.
  • O-GlcNAcylated MITF translocates to the nucleus, suppressing palbociclib-induced senescence.
  • Inhibition of MITF or O-GlcNAcylation restores sensitivity to palbociclib.
  • Activated MITF is observed in tumors from palbociclib-resistant patients.

Conclusions:

  • O-GlcNAcylation-mediated activation of MITF is a key mechanism driving palbociclib resistance in breast cancer.
  • Targeting MITF or its O-GlcNAcylation represents a promising strategy to re-sensitize resistant breast cancer to CDK4/6 inhibitors.
  • Clinical evidence supports MITF activation in palbociclib-resistant patient tumors, validating its therapeutic potential.

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