Question 1

What does HIF1A do in cancer?

Accepted Answer

HIF-1α is the oxygen-sensing subunit of HIF-1 that, under tumour hypoxia, drives transcription of VEGFA for angiogenesis, GLUT1 and HK2 for glycolysis, and invasion genes. It essentially reprogrammes tumour metabolism and vasculature to support survival and growth in low-oxygen conditions.

Question 2

How does VHL regulate HIF-1α?

Accepted Answer

In normoxia, prolyl hydroxylase domain (PHD) enzymes hydroxylate two prolines in HIF-1α, enabling recognition by the VHL E3 ubiquitin ligase for proteasomal degradation. Hypoxia inhibits PHDs (which require oxygen), stabilising HIF-1α. VHL mutations in clear cell renal carcinoma constitutively activate HIF-1/2α even in normoxia.

Question 3

What is the Warburg effect and how does HIF1A drive it?

Accepted Answer

The Warburg effect describes cancer cells preferring aerobic glycolysis — producing lactate even with abundant oxygen. HIF-1α transcriptionally upregulates glycolytic enzymes (LDHA, HK2, PKM2) and PDK1, which inhibits mitochondrial pyruvate oxidation. This metabolic shift meets the biosynthetic demands of rapid proliferation.

Question 4

Is HIF1A a drug target?

Accepted Answer

Belzutifan, a HIF-2α inhibitor, is approved for VHL disease-associated renal tumours and is in trials for sporadic clear cell RCC. Direct HIF-1α inhibition remains challenging, but anti-VEGF therapies (bevacizumab) and VEGFR inhibitors exploit HIF-1α-driven angiogenesis downstream, and PHD inhibitors manipulate the same axis in anaemia.

HIF1A Gene Function

Overview

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