Heat shock protein-90alpha (Hsp90α) stabilizes hypoxia-inducible factor-1α (HIF-1α) in support of spermatogenesis and tumorigenesis

Hypoxia-inducible factor-1 (HIF-1), a master transcriptional factor for protecting cells from hypoxia, plays a critical role in spermatogenesis and tumorigenesis. For the past two decades, numerous small molecule inhibitors that block mRNA synthesis, protein translation, or DNA binding of HIF-1 alpha have entered clinical trials. To date, few have advanced to FDA approval for clinical applications due to limited efficacy at their toxicity-tolerable dosages. New windows for developing effective and safe therapeutics require better understanding of the specific mechanism of action. The finding that a chaperone-defective mutant heat shock protein-90-alpha (Hsp90 alpha) blocks spermatogenesis, a known hypoxia-driven process in mouse testis prompted us to focus on the role of Hsp90 alpha in HIF-1 alpha. Here we demonstrate that Hsp90 alpha gene knockout causes a dramatic reduction of the high steady-state level of HIF-1 alpha in the testis, blocking sperm production and causing infertility of the mice. In HIF-1 alpha-dependent tumor cells, we found that Hsp90 alpha forms protein complexes with hypoxia-elevated HIF-1 alpha and Hsp90 alpha knockout prevents hypoxia-induced HIF-1 alpha accumulation. In contrast, downregulation of Hsp90 beta had little effect on hypoxia-induced accumulation of HIF-1 alpha. Instead, Hsp90 beta protects signaling molecules responsible for cellular homeostasis from assault by 17-AAG (17-N-allylamino-17-demethoxygeldanamycin), a general ATPase inhibitor of both Hsp90 alpha and Hsp90 beta. Since targeting Hsp90 beta gene is lethal in both cultured cells and in mice, our new finding explains the toxicity of the previous inhibitor trials and identifies the specific binding of Hsp90 alpha to HIF-1 alpha as a new therapeutic window for developing safer and more effective treatment of male infertility and cancer.

Automated summary

HIF-1 and Hsp90 play critical roles in spermatogenesis and tumorigenesis, with Hsp90 alpha affecting the levels of HIF-1 alpha in testis, and Hsp90 beta providing protection for signaling molecules responsible for cellular homeostasis.