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

Autor: Zhang Y; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Zhou S; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Kai Y; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Zhang YQ; Division of Preclinical Innovation (Intramural), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA., Peng C; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Li Z; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Mughal MJ; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Julie B; Department of Medicine, Washington University School of Medicine in St Louis, Siteman Cancer Center, St Louis, MO, USA., Zheng X; Department of Anatomy and Cell Biology, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA., Ma J; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Ma CX; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA., Shen M; Division of Preclinical Innovation (Intramural), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA., Hall MD; Division of Preclinical Innovation (Intramural), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA., Li S; Department of Medicine, Washington University School of Medicine in St Louis, Siteman Cancer Center, St Louis, MO, USA. shunqiangli@wustl.edu., Zhu W; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. wz6812@gwu.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 03; Vol. 15 (1), pp. 5597. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1038/s41467-024-49875-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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