EPAS1

Overview

EPAS1 encodes HIF2A (hypoxia-inducible factor 2 alpha), a transcription factor stabilized under hypoxic conditions when VHL-mediated proteasomal degradation is abrogated. In clear-cell renal cell carcinoma (ccRCC), biallelic VHL loss is the dominant truncal event; EPAS1-specific transcriptional programs drive extracellular matrix remodeling, motility, and secretion, as well as time-dependent dedifferentiation of proximal tubule cells.

Alterations observed in the corpus

  • Required for cortical/outer-medullary proximal tubule (PT) cell proliferation following Vhl inactivation in a murine ccRCC precursor model, but dispensable in the renal papilla; HIF2A-specific upregulation drives ECM/motility/secretion programs while HIF2A-specific downregulation drives dedifferentiation of PT cells over time PMID:23797736
  • Human ccRCC almost universally bears VHL mutation but rarely bears EPAS1 activating mutations; mechanistic explanation offered: HIF2A activation alone cannot regulate the HIF1A-specific glycolytic program required for early proliferative advantage PMID:23797736
  • Somatic hotspot mutations at A530, P531, Y532 drive HIF stabilization (pseudohypoxia) in pheochromocytoma/paraganglioma (PHC/PGNG); one of five MutSig2 significant somatic driver genes (q<0.05) in the TCGA PCPG study; completely specific to the pseudohypoxia mRNA subtype PMID:28162975.

Cancer types (linked)

  • CCRCC — HIF2A drives the dedifferentiation and adaptive transcriptional program that becomes prominent months after Vhl inactivation but before any morphological abnormality; TCGA cross-validation supports translational relevance PMID:23797736

Co-occurrence and mutual exclusivity

  • Works in concert with HIF1A downstream of VHL loss; HIF1A drives anti-survival effects in papilla and early proliferation in cortical PT cells via glycolytic targets, while HIF2A drives ECM/motility/dedifferentiation programs PMID:23797736
  • HIF2A cooperates with PAX8 to upregulate cyclin D1 (CCND1) in ccRCC (prior work cited) PMID:23797736
  • TFs HNF4A, HNF1B, and FOXA2 identified as mediators of HIF2A-specific transcriptional output at HIF2A-dependent gene loci PMID:23797736

Therapeutic relevance

  • Clinically approved HIF2A antagonist belzutifan nominated for early use in VHL disease to prevent expansion of Vhl-null PT cancer cells-of-origin before morphological abnormality PMID:23797736

Open questions

  • Complete mechanistic basis for the absence of activating EPAS1 mutations in ccRCC remains to be fully elucidated; current hypothesis is that HIF2A alone cannot drive the HIF1A-controlled glycolytic program needed for early proliferative advantage PMID:23797736

Sources

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