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USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis.
Gao, Ruize; Buechel, David; Kalathur, Ravi K R; Morini, Marco F; Coto-Llerena, Mairene; Ercan, Caner; Piscuoglio, Salvatore; Chen, Qian; Blumer, Tanja; Wang, Xueya; Dazert, Eva; Heim, Markus H; Hall, Michael N; Tang, Fengyuan; Christofori, Gerhard.
Afiliación
  • Gao R; Department of Biomedicine, University of Basel, Basel, Switzerland. ruize.gao@unibas.ch.
  • Buechel D; Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Kalathur RKR; Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Morini MF; Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Coto-Llerena M; Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Ercan C; Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Piscuoglio S; Institute of Pathology, University Hospital Basel, Basel, Switzerland.
  • Chen Q; Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Blumer T; University Hospital Basel, Basel, Switzerland.
  • Wang X; Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Dazert E; University Hospital Basel, Basel, Switzerland.
  • Heim MH; Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Hall MN; University Hospital Basel, Basel, Switzerland.
  • Tang F; Biozentrum, University of Basel, Basel, Switzerland.
  • Christofori G; Department of Biomedicine, University of Basel, Basel, Switzerland.
Oncogenesis ; 10(7): 52, 2021 Jul 16.
Article en En | MEDLINE | ID: mdl-34272356
Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Oncogenesis Año: 2021 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Oncogenesis Año: 2021 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos