Multiple Endocrine Neoplasia Type 1 Regulates TGFß-Mediated Suppression of Tumor Formation and Metastasis in Melanoma.
Cells
; 13(11)2024 Jun 04.
Article
en En
| MEDLINE
| ID: mdl-38891107
ABSTRACT
Over the past few decades, the worldwide incidence of cutaneous melanoma, a malignant neoplasm arising from melanocytes, has been increasing markedly, leading to the highest rate of skin cancer-related deaths. While localized tumors are easily removed by excision surgery, late-stage metastatic melanomas are refractory to treatment and exhibit a poor prognosis. Consequently, unraveling the molecular mechanisms underlying melanoma tumorigenesis and metastasis is crucial for developing novel targeted therapies. We found that the multiple endocrine neoplasia type 1 (MEN1) gene product Menin is required for the transforming growth factor beta (TGFß) signaling pathway to induce cell growth arrest and apoptosis in vitro and prevent tumorigenesis in vivo in preclinical xenograft models of melanoma. We further identified point mutations in two MEN1 family members affected by melanoma that led to proteasomal degradation of the MEN1 gene product and to a loss of TGFß signaling. Interestingly, blocking the proteasome degradation pathway using an FDA-approved drug and RNAi targeting could efficiently restore MEN1 expression and TGFß transcriptional responses. Together, these results provide new potential therapeutic strategies and patient stratification for the treatment of cutaneous melanoma.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Factor de Crecimiento Transformador beta
/
Melanoma
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cells
Año:
2024
Tipo del documento:
Article
País de afiliación:
Canadá