Journal Article

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

Kai, Yan, Li, Shunqiang, Zheng, Xiaoyan, Zhou, Shuyan, Zhang, Yi, Ma, Junfeng, Zhu, Wenge, Julie, Belmar, Hall, Matthew D., Zhang, Ya-qin, Shen, Min, Ma, Cynthia X., Li, Zhuqing, mughal, Muhammad Jameel, Peng, Changmin

2024

Overview

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. Targeting CDK4/6 in breast cancer has been demonstrated to be initially effective but often, resistance develops. Here, the authors identify microphthalmia-associated transcription factor-A (MITF-A) as a driver of CDK4/6 inhibitor resistance in breast cancer and show that MITF-A activity is mediated through O-GlcNAcylation at Serine 49, promoting its nuclear import.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 49 / 49/47 / 631/154/1435/2163 / 631/67/1347 / 631/80/458/1524 / 82/58 / Animals / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell activation / Cell cycle / Cell Line, Tumor / Combinatorial analysis / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - antagonists & inhibitors / Cyclin-Dependent Kinase 4 - metabolism / Cyclin-Dependent Kinase 6 - antagonists & inhibitors / Cyclin-Dependent Kinase 6 - metabolism / Cyclin-dependent kinases / Drug Resistance, Neoplasm - drug effects / Drug screening / Effectiveness / Female / Humanities and Social Sciences / Humans / Kinases / Mice / Microphthalmia-associated transcription factor / Microphthalmia-Associated Transcription Factor - genetics / Microphthalmia-Associated Transcription Factor - metabolism / multidisciplinary / N-Acetylglucosaminyltransferases - antagonists & inhibitors / N-Acetylglucosaminyltransferases - genetics / N-Acetylglucosaminyltransferases - metabolism / Nuclear transport / O-GlcNAcylation / Patients / Piperazines - pharmacology / Protein Kinase Inhibitors - pharmacology / Pyridines - pharmacology / Science / Science (multidisciplinary) / Senescence / Serine / Transcription factors / Translocation / Tumors / Whole genome sequencing / Xenograft Model Antitumor Assays