CHD1 deletion stabilizes HIF1a to promote angiogenesis and glycolysis in prostate cancer

Chromodomain-helicase-DNA-binding protein 1 (CHD1) deletion is among the most common mutations in prostate cancer (PCa), but its role remains unclear. In this study, RNA sequencing was conducted in PCa cells after clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-based CHD1 knockout. Gene set enrichment analysis (GSEA) indicated upregulation of hypoxia-related pathways. A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1 alpha (HIF1 alpha) expression. Mechanistic investigation revealed that CHD1 deletion upregulated HIF1 alpha by transcriptionally downregulating prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase catalyzing the hydroxylation of HIF1 alpha and thus promoting its degradation by the E3 ligase von Hippel-Lindau tumor suppressor (VHL). Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis, possibly through HIF1 alpha target genes. Taken together, these findings indicate that CHD1 deletion enhances HIF1 alpha expression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.