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This study investigated the role of EPAS1 (which encodes HIF-2α) in infantile hemangioma endothelial cells using both pharmacological inhibition and genetic knockdown approaches. EPAS1 knockdown reduced cell proliferation and altered cell cycle distribution, with changes in DNA replication and cell cycle gene programs, including reduced MYC and E2F signaling. Notably, these effects occurred similarly under both normal oxygen and low oxygen conditions, and analysis of hemangioma tissue showed reduced EGLN3 expression, suggesting that oxygen-independent mechanisms may help maintain HIF-2α activity in infantile hemangiomas.
Why it matters
Understanding the molecular mechanisms driving infantile hemangioma could lead to improved treatment strategies for this common benign tumor in infants. The finding that HIF-2α may function independently of oxygen levels in this context challenges conventional understanding and suggests that targeting this pathway might be therapeutically relevant regardless of tumor oxygenation status.
Understand the Science
by Zheren Su, Luying Wang, Ruixue Zhao, Zhiyu Li, Jing Li, Jianhai Bi, Ran Huo
Infantile hemangioma (IH) is the most common benign tumor of infancy. Hypoxia and activation of hypoxia-inducible factor (HIF) signaling have been proposed to contribute to IH pathogenesis, yet the role of endothelial PAS domain-containing protein 1 (EPAS1), which encodes hypoxia-inducible factor-2α (HIF-2α), in hemangioma endothelial cells (HemECs) remains less well characterized. Here, we investigated HIF-2α in primary HemECs using a pharmacological inhibitor (PT-2399) and shRNA-mediated EPAS1 knockdown under normoxic and hypoxic conditions. In hypoxic cultures, PT-2399 treatment was associated with reduced migration and invasion and with a reduction in junction number in tube formation assays; at the selected dose, PT-2399 did not significantly reduce cell viability. By contrast, EPAS1 knockdown was associated with reduced proliferative capacity and altered cell cycle distribution, together with enrichment of DNA replication/cell cycle-related transcriptional programs, negative enrichment of MYC- and E2F-related gene sets, and directionally consistent protein level changes in selected regulators. EPAS1 knockdown-associated phenotypic trends were broadly similar under normoxia and hypoxia, with no clear evidence that hypoxic stimulation enhanced the magnitude of these changes. In IH tissue transcriptomic data, Egl-9 family hypoxia-inducible factor 3 (EGLN3) showed reduced expression, consistent with a testable hypothesis that hypoxia-independent mechanisms may contribute to maintenance of HIF-2α activity in this context. This study is limited by the use of HemECs derived from a single IH specimen and by the absence of on-target validation; accordingly, the findings should be interpreted as exploratory and hypothesis-generating.