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

• Published in: Nature communications Vol. 15; no. 1; pp. 5597 - 17
• Main Authors: Zhang, Yi, Zhou, Shuyan, Kai, Yan, Zhang, Ya-qin, Peng, Changmin, Li, Zhuqing, mughal, Muhammad Jameel, Julie, Belmar, Zheng, Xiaoyan, Ma, Junfeng, Ma, Cynthia X., Shen, Min, Hall, Matthew D., Li, Shunqiang, Zhu, Wenge
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 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; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49875-w

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.