O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer
Document Type
Journal Article
Publication Date
10-3-2023
Journal
Research square
DOI
10.21203/rs.3.rs-3377962/v1
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 found 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; O-GlcNAcylation of MITF at Serine 49 enhanced its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppressed palbociclib-induced senescence; inhibition of MITF or its O-GlcNAcylation re-sensitized resistant cells to palbociclib. Remarkably, clinical studies confirmed the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on a novel mechanism regulating palbociclib-resistance, and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
APA Citation
Zhu, Wenge; Zhang, Y I.; Zhou, Shuyan; Kai, Yan; Zhang, Ya-Qin; Peng, Changmin; Li, Zhuqing; Mughal, Muhammad; Ma, Junfeng; Li, Shunqiang; Ma, Cynthia; Shen, Min; and Hall, Matthew, "O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer" (2023). GW Authored Works. Paper 3642.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3642
Department
Biochemistry and Molecular Medicine