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

Author

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  • Yi Zhang

    (George Washington University School of Medicine and Health Sciences)

  • Shuyan Zhou

    (George Washington University School of Medicine and Health Sciences)

  • Yan Kai

    (George Washington University School of Medicine and Health Sciences)

  • Ya-qin Zhang

    (National Center for Advancing Translational Sciences (NCATS), National Institutes of Health)

  • Changmin Peng

    (George Washington University School of Medicine and Health Sciences)

  • Zhuqing Li

    (George Washington University School of Medicine and Health Sciences)

  • Muhammad Jameel mughal

    (George Washington University School of Medicine and Health Sciences)

  • Belmar Julie

    (Siteman Cancer Center)

  • Xiaoyan Zheng

    (George Washington University School of Medicine and Health Sciences)

  • Junfeng Ma

    (Georgetown University Medical Center)

  • Cynthia X. Ma

    (Washington University School of Medicine)

  • Min Shen

    (National Center for Advancing Translational Sciences (NCATS), National Institutes of Health)

  • Matthew D. Hall

    (National Center for Advancing Translational Sciences (NCATS), National Institutes of Health)

  • Shunqiang Li

    (Siteman Cancer Center)

  • Wenge Zhu

    (George Washington University School of Medicine and Health Sciences)

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

Suggested Citation

  • Yi Zhang & Shuyan Zhou & Yan Kai & Ya-qin Zhang & Changmin Peng & Zhuqing Li & Muhammad Jameel mughal & Belmar Julie & Xiaoyan Zheng & Junfeng Ma & Cynthia X. Ma & Min Shen & Matthew D. Hall & Shunqia, 2024. "O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49875-w
    DOI: 10.1038/s41467-024-49875-w
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