Your browser doesn't support javascript.
loading
REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma.
Singh, Ashutosh; Cheng, Donghang; Swaminathan, Jyothishmathi; Yang, Yanwen; Zheng, Yan; Gordon, Nancy; Gopalakrishnan, Vidya.
Afiliação
  • Singh A; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
  • Cheng D; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
  • Swaminathan J; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
  • Yang Y; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
  • Zheng Y; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
  • Gordon N; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
  • Gopalakrishnan V; Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA. vgopalak@mdanderson.org.
Sci Rep ; 14(1): 13596, 2024 06 12.
Article em En | MEDLINE | ID: mdl-38866867
ABSTRACT
The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)-a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein - a component of an E3 ligase complex that ubiquitinates HIF1α. Human SHH-medulloblastoma tumors with higher REST expression exhibit nuclear localization of HIF1α, in contrast to its cytoplasmic localization in low-REST tumors. In vitro, REST knockdown promotes an increase in VHL levels and a decrease in cytoplasmic HIF1α protein levels, and autophagy flux. In contrast, REST elevation causes a decline in VHL levels, as well as its interaction with HIF1α, resulting in a reduction in HIF1α ubiquitination and an increase in autophagy flux. These data suggest that REST elevation promotes autophagy in SHH medulloblastoma cells by modulating HIF1α ubiquitination and stability in a VHL-dependent manner. Thus, our study is one of the first to connect VHL to REST-dependent control of autophagy in a subset of medulloblastomas.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Neoplasias Cerebelares / Proteína Supressora de Tumor Von Hippel-Lindau / Subunidade alfa do Fator 1 Induzível por Hipóxia / Proteínas Hedgehog / Meduloblastoma Limite: Animals / Humans Idioma: En Revista: Sci Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Neoplasias Cerebelares / Proteína Supressora de Tumor Von Hippel-Lindau / Subunidade alfa do Fator 1 Induzível por Hipóxia / Proteínas Hedgehog / Meduloblastoma Limite: Animals / Humans Idioma: En Revista: Sci Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos