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


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.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC11222436 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Zhang Yi Y   Zhou Shuyan S   Kai Yan Y   Zhang Ya-Qin YQ   Peng Changmin C   Li Zhuqing Z   Mughal Muhammad Jameel MJ   Julie Belmar B   Zheng Xiaoyan X   Ma Junfeng J   Ma Cynthia X CX   Shen Min M   Hall Matthew D MD   Li Shunqiang S   Zhu Wenge W  

Nature communications 20240703 1


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 transfe  ...[more]

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