Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss.
Mol Cell
; 77(6): 1294-1306.e5, 2020 03 19.
Article
en En
| MEDLINE
| ID: mdl-32023483
von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
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Carcinoma de Células Renales
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Biomarcadores de Tumor
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Regulación Neoplásica de la Expresión Génica
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Fosfotransferasas (Aceptor de Grupo Alcohol)
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Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau
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Neoplasias Renales
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
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Screening_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos