Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma.
EMBO J
; 37(21)2018 11 02.
Article
en En
| MEDLINE
| ID: mdl-30237309
ABSTRACT
The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR-15a. TSC1 knockdown results in elevated mTORC1-dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC-driven cancers.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Regulación Neoplásica de la Expresión Génica
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Proteínas Proto-Oncogénicas c-myc
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Linfoma de Burkitt
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Proteína 1 del Complejo de la Esclerosis Tuberosa
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Proteína 2 del Complejo de la Esclerosis Tuberosa
Límite:
Animals
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Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article