HIF-activated priming of TRAIL-induced cell death determines epigenetic vulnerability in kidney cancer

  • Cell Rep Med. 2026 Mar 17;7(3):102630. doi: 10.1016/j.xcrm.2026.102630.
Yong Wang  1 ,  Yan Xiong  2 ,  Shuiqiao Liu  1 ,  Lei Bao  1 ,  Xing Qiu  2 ,  Ilia Korboukh  2 ,  Xiangyang Song  2 ,  Vanina Toffessi Tcheuyap  3 ,  Sipeng Wu  1 ,  Mingyi Chen  1 ,  James Brugarolas  3 ,  Jian Jin  2 ,  Yingfei Wang  4 ,  Weibo Luo  5
Affiliations
  • 1. Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3. Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 5. Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 41713410 DOI: 10.1016/j.xcrm.2026.102630
Abstract

Activation of hypoxia-inducible factors (HIFs) supports Cancer cell survival, yet how HIFs govern cell death remains unclear, despite evidence that HIF-1 acts as a tumor suppressor in cell renal cell carcinoma (ccRCC). Here, we report a cell death-priming role for HIF-1/2 in ccRCC. Through cell viability screens with chemical libraries, we identify SGI1027 and its analog MS1129 as HIF-1/2-dependent cell death inducers that specifically kill VHL-deficient ccRCC cells in vitro and patient-derived xenografts in mice. Mechanistically, SGI1027 and MS1129 induce proteasomal degradation of DNMT1/DNMT3A/DNMT3B proteins, leading to the loss of promoter methylation and subsequent upregulation of TRAIL, DR4, and DR5 in ccRCC cells. HIF-1/2 induces procaspase-10 expression serving a commitment point to activate TRAIL-induced Apoptosis in VHL-deficient ccRCC following SGI1027 or MS1129 treatment. Notably, recombinant TRAIL protein synergizes with SGI1027 or MS1129 to kill VHL-deficient ccRCC in mice. Collectively, our study unveils an Apoptosis induction strategy that involves hijacking HIFs for ccRCC treatment.

Keywords
DNMT; HIF; TRAIL; VHL; cell death priming; death receptors; epigenetic vulnerability.
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