O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.
Nat Commun
; 15(1): 5597, 2024 Jul 03.
Article
em En
| MEDLINE
| ID: mdl-38961064
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/ß, 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Piridinas
/
Neoplasias da Mama
/
N-Acetilglucosaminiltransferases
/
Resistencia a Medicamentos Antineoplásicos
/
Quinase 4 Dependente de Ciclina
/
Quinase 6 Dependente de Ciclina
/
Fator de Transcrição Associado à Microftalmia
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos