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Enhancer-Mediated Regulation of HIF-2α by the SOCS3–JAK1–STAT3 Axis in Renal Cancer

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is characterized by frequent loss of the von Hippel–Lindau (VHL) tumor suppressor, leading to pathological accumulation of hypoxia-inducible factor 2α (HIF-2α). Although direct HIF-2α inhibitors such as Belzutifan have shown clinical efficacy, therapeutic resistance remains a major challenge. To uncover additional regulatory mechanisms governing HIF-2α activity, we performed a genome-wide CRISPR screen in VHL-deficient ccRCC cells. This revealed the TREX mRNA export complex as a positive regulator and Suppressor of Cytokine Signaling 3 (SOCS3) as the most significant negative regulator of HIF-2α. We demonstrate that SOCS3 suppresses HIF-2α expression through inhibition of the JAK1–STAT3 signaling axis. Loss of SOCS3 activates STAT3, which directly binds to enhancers upstream of the EPAS1 (HIF-2α) gene, promoting its transcription. SOCS3 overexpression or JAK1/STAT3 inhibition suppresses HIF-2α levels, impairs tumor growth, and reduces metastasis in ccRCC models. These findings define a novel SOCS3–JAK1–STAT3–HIF-2α regulatory axis and identify enhancer-mediated transcriptional control as a critical mechanism of HIF-2α regulation. Targeting this pathway offers a promising strategy to overcome resistance to current HIF-2α inhibitors and improve therapeutic outcomes in ccRCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303721 | GEO | 2026/02/06

REPOSITORIES: GEO

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Project description:To identify the precise molecular mechanisms that could contribute to the increase in colon carcinogenesis, microarray gene expression analysis was performed on colon RNA isolated from 5-week-old VhlF/F and VhlΔIE, VhlΔIE/Apcmin/+ and VhlF/F/Apcmin/+ mice. Hypoxia-inducible factor (HIF) is a key modulator of the transcriptional response to hypoxia and is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. Intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and Hif-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue, however tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, BrdU incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis demonstrated that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings demonstrate that a chronic increase in HIF-2α in the colon initiates pro-tumorigenic signaling which may have important implications in developing preventive and therapeutic strategies for colon cancer. Global gene expression profiling in colon RNAs isolated from 5-week-old VhlF/F (n=4, Shah 001), VhlF/F/Apcmin/+(n=3, Shah 003), VhlΔIE (n=3, Shah 002) and VhlΔIE/Apcmin/+ mice (n=5, Shah 004).

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Enhancer-Mediated Regulation of HIF-2α by the SOCS3–JAK1–STAT3 Axis in Renal Cancer

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