MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex.
Proc Natl Acad Sci U S A
; 118(37)2021 09 14.
Article
en En
| MEDLINE
| ID: mdl-34493659
ABSTRACT
The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.
Palabras clave
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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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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice
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Carcinoma Pulmonar de Células Pequeñas
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Proteínas del Grupo Polycomb
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Neoplasias Pulmonares
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article