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

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.

Department

Biochemistry and Molecular Medicine

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