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

Authors

• Yi Zhang, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Shuyan Zhou, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Yan Kai, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Ya-Qin Zhang, Division of Preclinical Innovation (Intramural), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA.
• Changmin Peng, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Zhuqing Li, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Muhammad Jameel Mughal, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Belmar Julie, Department of Medicine, Washington University School of Medicine in St Louis, Siteman Cancer Center, St Louis, MO, USA.
• Xiaoyan Zheng, Department of Anatomy and Cell Biology, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
• Junfeng Ma, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
• Cynthia X. Ma, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
• Min Shen, Division of Preclinical Innovation (Intramural), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA.
• Matthew D. Hall, Division of Preclinical Innovation (Intramural), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA.
• Shunqiang Li, Department of Medicine, Washington University School of Medicine in St Louis, Siteman Cancer Center, St Louis, MO, USA. shunqiangli@wustl.edu.
• Wenge Zhu, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. wz6812@gwu.edu.

Document Type

Journal Article

Publication Date

7-3-2024

Journal

Nature communications

Volume

15

Issue

1

DOI

10.1038/s41467-024-49875-w

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.

APA Citation

Zhang, Yi; Zhou, Shuyan; Kai, Yan; Zhang, Ya-Qin; Peng, Changmin; Li, Zhuqing; Mughal, Muhammad Jameel; Julie, Belmar; Zheng, Xiaoyan; Ma, Junfeng; Ma, Cynthia X.; Shen, Min; Hall, Matthew D.; Li, Shunqiang; and Zhu, Wenge, "O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer" (2024). GW Authored Works. Paper 5329.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/5329

Department

Biochemistry and Molecular Medicine