RESUMEN
Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. SIGNIFICANCE: These findings characterize FBXW7 as a prosurvival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Proteínas de Neoplasias/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Cromatina/metabolismo , Proteínas de Unión al ADN/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Técnicas de Inactivación de Genes , Células HEK293 , Humanos , Linfoma de Células B Grandes Difuso/patología , Ratones , Proteínas de Neoplasias/genética , Fosforilación Oxidativa , Proteolisis , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Ubiquitina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Triple-negative breast cancer (TNBC) is characterized by a high degree of immune infiltrate in the tumour microenvironment, which may influence the fate of TNBC cells. We reveal that loss of the tumour suppressive transcription factor Elf5 in TNBC cells activates intrinsic interferon-γ (IFN-γ) signalling, promoting tumour progression and metastasis. Mechanistically, we find that loss of the Elf5-regulated ubiquitin ligase FBXW7 ensures stabilization of its putative protein substrate IFN-γ receptor 1 (IFNGR1) at the protein level in TNBC. Elf5low tumours show enhanced IFN-γ signalling accompanied by an increase of immunosuppressive neutrophils within the tumour microenvironment and increased programmed death ligand 1 expression. Inactivation of either programmed death ligand 1 or IFNGR1 elicited a robust anti-tumour and/or anti-metastatic effect. A positive correlation between ELF5 and FBXW7 expression and a negative correlation between ELF5, FBXW7 and IFNGR1 expression in the tumours of patients with TNBC strongly suggest that this signalling axis could be exploited for patient stratification and immunotherapeutic treatment strategies for Elf5low patients with TNBC.
Asunto(s)
Proliferación Celular/fisiología , Proteínas de Unión al ADN/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Interferón gamma/metabolismo , Metástasis de la Neoplasia/patología , Receptores de Interferón/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Transducción de Señal/fisiología , Microambiente Tumoral/fisiología , Receptor de Interferón gammaRESUMEN
Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D (MLL4) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.
