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Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis

Oncogene volume 36, pages 6555–6567 (2017)Cite this article

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Abstract

The cellular prion protein (PrPC) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrPC degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrPC accumulation and tumorigenicity in vivo. PrPC was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrPC. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrPC, thereby increasing PrPC ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrPC, thereby revealing an essential mechanism that controls PrPC levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrPC accumulation during tumor progression.

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Acknowledgements

This work was supported by the Soonchunhyang University Research Fund; a National Research Foundation grant funded by the Korean government (NRF-2011-0009610); NRF funded by the Ministry of Education (2016R1D1A3B01007727, 2017M3A9B4032528); a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI14C2253); and a grant from the Next-Generation Bio-Green 21 Program (No. PJ011141), Rural Development Administration, Republic of Korea. The funders had no role in the study design, data collection or analysis, decision to publish or preparation of the manuscript.

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  1. J H Lee and Y-S Han: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA

    J H Lee

  2. Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea

    Y-S Han, Y M Yoon, C W Yun & S H Lee

  3. Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea

    Y-S Han, Y M Yoon, C W Yun & S H Lee

  4. Institute for Cell Engineering Department of Neurology, Neuroregeneration and Stem Cell Programs, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    S P Yun & S M Kim

  5. Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea

    H Y Kwon

  6. Department of Pathology, Collage of Medicine, Soonchunhyang University, Cheonan, Republic of Korea

    D Jeong

  7. Department of Surgery, Collage of Medicine, Soonchunhyang University, Cheonan, Republic of Korea

    M J Baek

  8. Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Republic of Korea

    H J Lee, S-J Lee & H J Han

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Lee, J., Han, YS., Yoon, Y. et al. Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis. Oncogene 36, 6555–6567 (2017). https://doi.org/10.1038/onc.2017.263

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