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Cancer Res ; 80(14): 3009-3022, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32366477

RESUMEN

HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of HACE1 has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that HACE1 is frequently mutated in human lung cancer. In mice, loss of Hace1 led to enhanced progression of KRasG12D -driven lung tumors. Additional ablation of the oncogenic GTPase Rac1 partially reduced progression of Hace1-/- lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in Hace1-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both Rac1 and Rac2 fully averted the increased progression of KRasG12D -driven lung tumors in Hace1-/- mice. In patients with lung cancer, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, whereas elevated expression of RAC1 and RAC2 was associated with poor prognosis. This work defines HACE1 as a crucial regulator of the oncogenic activity of RAC-family GTPases in lung cancer development. SIGNIFICANCE: These findings reveal that mutation of the tumor suppressor HACE1 disrupts its role as a regulator of the oncogenic activity of RAC-family GTPases in human and murine lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/14/3009/F1.large.jpg.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinogénesis/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/prevención & control , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Unión al GTP rac/antagonistas & inhibidores , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinogénesis/patología , Proliferación Celular , Humanos , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pronóstico , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Proteína RCA2 de Unión a GTP
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