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Abstract: FR-PO1027

p300/CBP-Associated Factor (PCAF) Modulates HIF-1 Activity at Multiple Steps

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Kurata, Yu, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo-ku, Tokyo, Japan
  • Sugahara, Mai, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo-ku, Tokyo, Japan
  • Tanaka, Tetsuhiro, Tohoku Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Sendai, Miyagi, Japan
  • Nangaku, Masaomi, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo-ku, Tokyo, Japan

Hypoxia-inducible factor (HIF) is a transcription factor that mediates the cellular response to hypoxia. The activity of HIF may be inadequate relative to the degree of hypoxia in patients with chronic kidney disease (CKD), resulting in impaired cellular adaptation to hypoxia. p300/CBP-associated factor (PCAF) is a transcriptional coactivator and has acetyltransferase activity. Recent studies have suggested that PCAF expression is downregulated in patients with end-stage kidney disease (ESKD). We aimed to elucidate the relationship between PCAF and HIF-1 in the kidney.


We subjected human kidney-2 (HK-2) cells, a human proximal tubular cell line, to hypoxia and examined the association between PCAF and HIF-1 by qPCR, western blotting, microarray analysis, hypoxia-responsive element-luciferase (HRE-luc) reporter assay, and Gal4 responsive element-luciferase (GRE-luc) reporter assay. GRE-luc assay employed a vector encoding Gal4 DNA binding domain (DBD)-HIF-1α transactivation domain (TAD) fusion protein and a GRE-driven luciferase reporter vector.


Knockdown (KD) of PCAF resulted in decreased expression levels of HIF-1α protein and VEGF mRNA, one of the major HIF-1 target genes. The HRE-luc assay revealed that PCAF KD reduced HIF-1 transcriptional activity. The GRE-luc assay showed the inhibition of HIF-1α TAD activity by PCAF KD. Overexpression of full-length PCAF upregulated GRE-luc activity, whereas a mutant PCAF lacking the histone acetyltransferase (HAT) domain failed to increase GRE-luc activity, indicating that the HAT domain was necessary for the regulation of HIF-1α TAD activity. Additionally, PCAF KD led to decreased mRNA and protein levels of ARNT, a binding partner of HIF-1α, and inhibited the interaction between HIF-1α and ARNT. Transcriptome analysis using microarray revealed that PCAF KD globally downregulated the expression of hypoxia-inducible genes.


Our findings demonstrate that PCAF modulates HIF-1 activity at multiple steps and serves as a global positive regulator for HIF-1.


  • Government Support – Non-U.S.