Degradation of HIF-1α by Hypericin

Hypoxia inducible factor (HIF) regulates processes such as cell proliferation and metabolism, and it has been implicated in tumour growth in several disorders such as VHL and TSC. Preston et al. (2010) demonstrated that HIF-1α activity was increased in FLCN-null cells and that there was an increase in the transcription of HIF target genes such as VEGF and GLUT1. This suggests that tumourigenesis in BHD syndrome may also result from the dysregulation of HIF.

Several HIF inhibitors have previously been described, such as Trichostatin A (Kong et al., 2006) and 17-AAG (Isaacs et al., 2002). Trichostatin A is a HDAC inhibitor which inhibits the acetylation of HIF (see this previous blog post) whereas 17-AAG inhibits the molecular chaperone Hsp90, which leads to the destabilisation of HIF. Barliya et al. (2011) have recently described another HIF-1α inhibitor called hypericin, which accelerates the degradation of HIF-1α through a unique mechanism and looks promising as an anti-cancer therapy.

Hypericin-mediated HIF-1α degradation was shown in two human tumour cell lines, U87-MG glioblastoma and RCC-C2VHL-/- renal cell carcinoma, and also a non-malignant ARPE19 retinal pigment epithelial cell line. The reduction in HIF-1α protein levels was shown to occur independently of cellular oxygen levels, VHL and the ubiquitination-proteasome pathway. A cathepsin-B inhibitor prevented HIF-1α degradation by hypericin, suggesting cathepsin-B-mediated degradation was occurring. Hypericin is known to reduce intracellular pH, which creates the optimal conditions for cathepsin activity. Barliya et al. confirmed this by stabilising the pH and observing less HIF-1α degradation.

Hypericin was previously reported to induce forced poly-ubiquitination of Hsp90, leading to its enhanced degradation and therefore also the destabilisation and degradation of Hsp90 client proteins (Blank et al., 2003). As HIF-1α is transported into the nucleus via Hsp90, the authors investigated how HIF is affected by the hypericin-mediated degradation of Hsp90. As expected, the degradation of Hsp90 prevents HIF-1α transport into the nucleus. Therefore hypericin has two effects on HIF: enhancing its degradation by activating cathepsin-B and also preventing its nuclear localisation by ubiquitination of Hsp90.

The degradation of HIF-1α prevents HIF binding to DNA. In the presence of hypericin, reduced binding of HIF to the VEGF and GLUT1 promoter regions was observed. A luciferase assay also showed reduced VEGF promoter activity in hypoxic conditions in the presence of hypericin.

A Phase I/II clinical trial using hypericin for the treatment of glioblastoma multiforme and anaplastic astrocytoma has been completed, showing promising results. Barliya et al. now suggest hypericin should be evaluated as a treatment in other cancers in which high levels of HIF cause tumourigenesis. It would certainly be interesting to study the effect of hypericin in FLCN-null cells.


  • Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73 PMID: 21057536
  • Barliya T, Mandel M, Livnat T, Weinberger D, & Lavie G (2011). Degradation of HIF-1alpha under hypoxia combined with induction of Hsp90 polyubiquitination in cancer cells by hypericin: a unique cancer therapy. PloS one, 6 (9) PMID: 21949677
  • Blank M, Mandel M, Keisari Y, Meruelo D, & Lavie G (2003). Enhanced ubiquitinylation of heat shock protein 90 as a potential mechanism for mitotic cell death in cancer cells induced with hypericin. Cancer research, 63 (23), 8241-7 PMID: 14678981
  • Kong X, Lin Z, Liang D, Fath D, Sang N, & Caro J (2006). Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Molecular and cellular biology, 26 (6), 2019-28 PMID: 16507982
  • Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, & Neckers LM (2002). Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. The Journal of biological chemistry, 277 (33), 29936-44 PMID: 12052835

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