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HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.
Bacigalupa, Zachary A; Arner, Emily N; Vlach, Logan M; Wolf, Melissa M; Brown, Whitney A; Krystofiak, Evan S; Ye, Xiang; Hongo, Rachel A; Landis, Madelyn; Amason, Edith K; Beckermann, Kathryn E; Rathmell, W Kimryn; Rathmell, Jeffrey C.
Afiliación
  • Bacigalupa ZA; Department of Medicine.
  • Arner EN; Department of Pathology, Microbiology, and Immunology, and.
  • Vlach LM; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Wolf MM; Department of Medicine.
  • Brown WA; Department of Pathology, Microbiology, and Immunology, and.
  • Krystofiak ES; Department of Medicine.
  • Ye X; Department of Medicine.
  • Hongo RA; Department of Pathology, Microbiology, and Immunology, and.
  • Landis M; Department of Medicine.
  • Amason EK; Cell Imaging Shared Resource, Vanderbilt University, Nashville, Tennessee, USA.
  • Beckermann KE; Department of Pathology, Microbiology, and Immunology, and.
  • Rathmell WK; Department of Medicine.
  • Rathmell JC; Department of Pathology, Microbiology, and Immunology, and.
J Clin Invest ; 134(12)2024 Jun 17.
Article en En | MEDLINE | ID: mdl-38941296
ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acetato CoA Ligasa / Carcinoma de Células Renales / Transducción de Señal / Regulación Neoplásica de la Expresión Génica / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Neoplasias Renales Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acetato CoA Ligasa / Carcinoma de Células Renales / Transducción de Señal / Regulación Neoplásica de la Expresión Génica / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Neoplasias Renales Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos