The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.
Cell Rep
; 26(2): 415-428.e5, 2019 01 08.
Article
en En
| MEDLINE
| ID: mdl-30625324
ABSTRACT
We identified a regulatory system that acts downstream of Wnt/ß-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/ß-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias de las Glándulas Salivales
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N-Metiltransferasa de Histona-Lisina
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Epigénesis Genética
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Código de Histonas
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Proteína de la Leucemia Mieloide-Linfoide
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Vía de Señalización Wnt
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Neoplasias de Cabeza y Cuello
Límite:
Animals
Idioma:
En
Revista:
Cell Rep
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania