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

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, Shunqiang Li () and Wenge Zhu ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49875-w

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