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

Cancer Gene Therapy volume 28, pages 1058–1070 (2021)Cite this article

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A Correction to this article was published on 19 April 2021

A Correction to this article was published on 19 April 2021

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Abstract

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-1α 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 (Hsp90α) blocks spermatogenesis, a known hypoxia-driven process in mouse testis prompted us to focus on the role of Hsp90α in HIF-1α. Here we demonstrate that Hsp90α gene knockout causes a dramatic reduction of the high steady-state level of HIF-1α in the testis, blocking sperm production and causing infertility of the mice. In HIF-1α-dependent tumor cells, we found that Hsp90α forms protein complexes with hypoxia-elevated HIF-1α and Hsp90α knockout prevents hypoxia-induced HIF-1α accumulation. In contrast, downregulation of Hsp90β had little effect on hypoxia-induced accumulation of HIF-1α. Instead, Hsp90β protects signaling molecules responsible for cellular homeostasis from assault by 17-AAG (17-N-allylamino-17-demethoxygeldanamycin), a general ATPase inhibitor of both Hsp90α and Hsp90β. Since targeting Hsp90β 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 Hsp90α to HIF-1α as a new therapeutic window for developing safer and more effective treatment of male infertility and cancer.

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Fig. 1: Generation of Hsp90α gene-knockout mice.
Fig. 2: Hsp90α gene knockout destabilizes HIF-1α in mouse testis.
Fig. 3: Hsp90α knockout prevents HIF-1α accumulation in tumor cells in response to hypoxia.
Fig. 4: Hsp90α and Hsp90β on HIF-1α stability in different cellular contexts.
Fig. 5: More Hsp90α protects HIF-1α than Hsp90β in intact cells.
Fig. 6: Hsp90α-knockout or knockdown has little effect on signaling pathways for cell survival and proliferation.
Fig. 7: Hsp90β protects key signaling molecules for homeostasis under 17-AAG assault.

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Acknowledgements

We have neither financial nor non-financial conflict of interest. This work is supported by NIH grants GM067100 (to W. L.), and grant W81XWH-1810558 from the Congressionally Directed Medical Research Program (to M. C.).

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  1. These authors contributed equally: Xin Tang, Cheng Chang

Authors and Affiliations

  1. Department of Dermatology and the Norris Comprehensive Cancer Centre, University of Southern California Keck Medical Center, Los Angeles, CA, USA

    Xin Tang, Cheng Chang, Michelle Hao, Mei Chen, David T. Woodley & Wei Li

  2. Department of Molecular Microbiology & Immunology, University of Southern California Keck Medical Center, Los Angeles, CA, USA

    Axel H. Schönthal

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  1. Xin Tang
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Correspondence to Wei Li.

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Tang, X., Chang, C., Hao, M. et al. Heat shock protein-90alpha (Hsp90α) stabilizes hypoxia-inducible factor-1α (HIF-1α) in support of spermatogenesis and tumorigenesis. Cancer Gene Ther 28, 1058–1070 (2021). https://doi.org/10.1038/s41417-021-00316-6

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