Summary of project PR001430
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001430. The data can be accessed directly via it's Project DOI: 10.21228/M8W69F This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001430 |
| Project DOI: | doi: 10.21228/M8W69F |
| Project Title: | ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma |
| Project Type: | Untargeted Metabolomics analysis |
| Project Summary: | Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer driven by VHL loss and aberrant HIF-2α signaling. Acetate metabolism may contribute to this axis by ACSS2-dependent acetylation of HIF-2α and may provide opportunities to intervention. Here we tested the effects of pharmacological and genetic manipulation of ACSS2 on HIF-2α, ccRCC cells, and tumors. ACSS2 inhibition led to HIF-2α degradation and suppressed ccRCC growth in vitro, in vivo, and in primary cell cultures of ccRCC patient tumors. This treatment resulted in reduced glucose and cholesterol metabolism, mitochondrial biogenesis and altered cristae deformation, that are consistent with loss of HIF-2α. Mechanistically, HIF-2α protein levels are regulated through proteolytic degradation and we found, in parallel to VHL, HIF-2α stability was dependent on ACSS2 activity to prevent direct interaction with the E3 ligase MUL1. These findings highlight ACSS2 as a critical upstream regulator of pathogenically stabilized HIF-2α, and provides a mechanism that may be exploited to overcome resistance to HIF-2α inhibitor therapies. |
| Institute: | Vanderbilt University |
| Department: | Chemistry |
| Laboratory: | Center for Innovative Technology |
| Last Name: | CODREANU |
| First Name: | SIMONA |
| Address: | 1234 STEVENSON CENTER LANE |
| Email: | SIMONA.CODREANU@VANDERBILT.EDU |
| Phone: | 16158758422 |
Summary of all studies in project PR001430
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST002241 | ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma | Mus musculus | Vanderbilt University | MS* | 2023-08-01 | 1 | 10 | Uploaded data (5.7G)* |
