2. Academic Validation
  3. HIF-activated priming of TRAIL-induced cell death determines epigenetic vulnerability in kidney cancer

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

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: yingfei.wang@utsouthwestern.edu.
  • 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: weibo.luo@utsouthwestern.edu.
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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