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ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma

Zachary A. Bacigalupa, Whitney A. Brown, Evan S. Krystofiak, Melissa M. Wolf, Rachel A. Hongo, Madelyn Landis, Edith K. Amason, Kathryn E. Beckermann, Jeffrey C. Rathmell, W. Kimryn Rathmell
doi: https://doi.org/10.1101/2022.04.21.489116
Zachary A. Bacigalupa
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
2Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232
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Whitney A. Brown
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Evan S. Krystofiak
3Cell Imaging Shared Resource, Vanderbilt University, Nashville, TN 37232
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Melissa M. Wolf
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Rachel A. Hongo
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
2Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232
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Madelyn Landis
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
2Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232
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Edith K. Amason
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Kathryn E. Beckermann
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Jeffrey C. Rathmell
2Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232
4Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
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W. Kimryn Rathmell
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
2Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232
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  • For correspondence: Kimryn.Rathmell@VUMC.org
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ABSTRACT

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 HIF-2α that may be exploited to overcome resistance to HIF-2α inhibitor therapies.

STATEMENT OF SIGNIFICANCE We have unveiled ACSS2 as a critical upstream regulator of HIF-2α in ccRCC. Targeting ACSS2 potently promotes HIF-2α degradation via MUL1 to effectively deplete mitochondrial activity and block ccRCC primary tumor models and growth models resistant to HIF-2α inhibitor therapy.

Competing Interest Statement

WKR received an unrestricted grant from the VICC and support from the VICC-Incyte alliance JCR is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics, a scientific advisory board member and stockholder of Caribou Biosciences, a member of the scientific advisory board of Nirogy Therapeutics, has consulted for Merck, Pfizer, and Mitobridge within the past three years, and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. KEB has received funding to the institution from BMS-IASLC-LCFA, consulted for Aravive, and served on the advisory board for Aveo, BMS, Exelexis, and Seagen. The remaining co-authors have no conflicts to disclose.

Footnotes

  • Figure 5 revised to include scale bars on images. Text for Figure 5 updated. Figure 5 legend has been updated.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 25, 2022.
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ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma
Zachary A. Bacigalupa, Whitney A. Brown, Evan S. Krystofiak, Melissa M. Wolf, Rachel A. Hongo, Madelyn Landis, Edith K. Amason, Kathryn E. Beckermann, Jeffrey C. Rathmell, W. Kimryn Rathmell
bioRxiv 2022.04.21.489116; doi: https://doi.org/10.1101/2022.04.21.489116
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ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma
Zachary A. Bacigalupa, Whitney A. Brown, Evan S. Krystofiak, Melissa M. Wolf, Rachel A. Hongo, Madelyn Landis, Edith K. Amason, Kathryn E. Beckermann, Jeffrey C. Rathmell, W. Kimryn Rathmell
bioRxiv 2022.04.21.489116; doi: https://doi.org/10.1101/2022.04.21.489116

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