HIF1A

Overview

HIF1A (Hypoxia-Inducible Factor 1-Alpha) encodes the alpha subunit of the HIF-1 transcription factor complex, which is a master regulator of cellular response to hypoxia. In clear cell renal cell carcinoma (ccRCC), the VHL tumor suppressor normally targets HIFα subunits for proteasomal degradation; VHL loss leads to constitutive HIF1A (and HIF2A/EPAS1) stabilization, driving glycolytic gene programs and oncogenesis. HIF1A plays context-dependent roles: it is required for early proliferative advantage in proximal tubule cells after VHL loss, but drives anti-survival effects in papillary renal cells.

Alterations observed in the corpus

  • Frequently lost via 14q deletion in 45% of clear cell renal cell carcinoma (ccRCC) samples; predicted to drive aggressive disease through HIF pathway dysregulation PMID:23792563
  • In a mouse VHL-knockout model, HIF1A stabilization drives anti-survival effects in the renal papilla but is required for early proliferation in cortical/outer-medullary proximal tubule cells; HIF1A-specific upregulated targets are dominated by glycolytic genes PMID:23797736
  • Referenced among COSMIC hotspot mutation genes identified as potential drug targets across non-clear cell RCC; upregulated as a downstream target of the ACTG1-MITF fusion in pRCC PMID:25401301

Cancer types (linked)

  • CCRCC: 14q (HIF1A locus) deletion in 45% of tumors; loss associated with aggressive phenotype. In VHL-null mouse models, HIF1A is required for early proximal tubule cell proliferation.

Co-occurrence and mutual exclusivity

  • Loss of HIF1A (14q deletion) occurs in the context of VHL mutation/methylation in ccRCC; cooperates with EPAS1 (HIF2A) in driving the full oncogenic program after VHL inactivation PMID:23797736

Therapeutic relevance

  • HIF2A inhibitor belzutifan (targeting EPAS1) is clinically approved in VHL disease; the asymmetric roles of HIF1A and HIF2A suggest HIF1A controls early glycolytic proliferation while HIF2A drives later dedifferentiation — relevant for timing of targeted intervention PMID:23797736

Open questions

  • Whether 14q deletion frequency in ccRCC reflects selection for HIF1A loss or co-deletion of nearby tumor suppressors is unresolved PMID:23792563
  • Why HIF2A-dependent transcriptional changes take months to manifest after VHL loss, while HIF1A effects are more immediate, remains mechanistically unexplained PMID:23797736

Sources

This page was processed by crosslinker on 2026-05-09. - PMID:25401301

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