| Autor: |
Bacigalupa ZA; Department of Medicine.; Department of Pathology, Microbiology, and Immunology, and.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Arner EN; Department of Medicine.; Department of Pathology, Microbiology, and Immunology, and., Vlach LM; Department of Medicine., Wolf MM; Department of Medicine.; Department of Pathology, Microbiology, and Immunology, and., Brown WA; Department of Medicine., Krystofiak ES; Cell Imaging Shared Resource, Vanderbilt University, Nashville, Tennessee, USA., Ye X; Department of Pathology, Microbiology, and Immunology, and., Hongo RA; Department of Medicine.; Department of Pathology, Microbiology, and Immunology, and., Landis M; Department of Medicine.; Department of Pathology, Microbiology, and Immunology, and., Amason EK; Department of Medicine., Beckermann KE; Department of Medicine., Rathmell WK; Department of Medicine.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Rathmell JC; Department of Pathology, Microbiology, and Immunology, and.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. |
| Abstrakt: |
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. |
