%0 Journal Article
%T O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.
%A Zhang Y
%A Zhou S
%A Kai Y
%A Zhang YQ
%A Peng C
%A Li Z
%A Mughal MJ
%A Julie B
%A Zheng X
%A Ma J
%A Ma CX
%A Shen M
%A Hall MD
%A Li S
%A Zhu W
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 3
%M 38961064
%F 17.694
%R 10.1038/s41467-024-49875-w
%X 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.