KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia

  1. Rajnish Kumar singh
  2. Yonggang Pei
  3. Dipayan Bose
  4. Zachary L Lamplugh
  5. Kunfeng Sun
  6. Yan Yuan
  7. Paul Lieberman
  8. Jianxin You
  9. Erle S Robertson  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Wistar, United States

Abstract

The cellular adaptive response to hypoxia, mediated by high HIF1α levels includes metabolic reprogramming, restricted DNA replication and cell division. In contrast to healthy cells, the genome of cancer cells, and Kaposi's sarcoma associated herpesvirus (KSHV) infected cells maintains replication in hypoxia. We show that KSHV infection, despite promoting expression of HIF1α in normoxia, can also restrict transcriptional activity, and promoted its degradation in hypoxia. KSHV-encoded vCyclin, expressed in hypoxia, mediated HIF1a cytosolic translocation, and its degradation through a non-canonical lysosomal pathway. Attenuation of HIF1α levels by vCyclin allowed cells to bypass the block to DNA replication and cell proliferation in hypoxia. These results demonstrated that KSHV utilizes a unique strategy to balance HIF1α levels to overcome replication arrest and induction of the oncogenic phenotype, which are dependent on the levels of oxygen in the microenvironment.

Data availability

The ChIP sequencing data has been submitted to GEO with accession number GSE149401. All data generated and analysed in this study are included in the manuscript and supporting files. Source data files have been provided for Figures: 1D, 2A, 2B, 2C, 6B and 6C. Also, source data file has been provided for supplementary Figures: Suppl. Fig. 1A, 1B, 1D, 1E , 1F, Suppl. Fig. 2A, 2B, 2C, Suppl. Fig. 5B and 5D.

The following data sets were generated

Article and author information

Author details

  1. Rajnish Kumar singh

    Otorhinolaryngology, University of Pennsylvania, 3610 Hamilton walk, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7414-1170
  2. Yonggang Pei

    Otorhinolaryngology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7296-8772
  3. Dipayan Bose

    Otorhinolaryngology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zachary L Lamplugh

    Otorhinolaryngology, University of Pennsylvania, 202B Johnson pavilion, 3610 Hamilton walk, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3442-0591
  5. Kunfeng Sun

    Otorhinolaryngology, University of Pennsylvania, 202B Johnson pavilion, 3610 Hamilton walk, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3874-8909
  6. Yan Yuan

    Penn Dental Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Paul Lieberman

    Gene Expression and Regulation, Wistar, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jianxin You

    Department of Microbiology, University of Pennsylvania, philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Erle S Robertson

    Otorhinolaryngology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    erle@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6088-2979

Funding

National Cancer Institute (P30-CA016520)

  • Erle S Robertson

National Cancer Institute (P01-CA174439)

  • Erle S Robertson

National Cancer Institute (U54-CA190158)

  • Erle S Robertson

National Cancer Institute (R01-CA171979)

  • Erle S Robertson

National Cancer Institute (R01-CA244074)

  • Erle S Robertson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Publication history

  1. Received: March 31, 2020
  2. Preprint posted: August 12, 2020 (view preprint)
  3. Accepted: July 17, 2021
  4. Accepted Manuscript published: July 19, 2021 (version 1)
  5. Version of Record published: July 27, 2021 (version 2)

Copyright

© 2021, singh et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rajnish Kumar singh
  2. Yonggang Pei
  3. Dipayan Bose
  4. Zachary L Lamplugh
  5. Kunfeng Sun
  6. Yan Yuan
  7. Paul Lieberman
  8. Jianxin You
  9. Erle S Robertson
(2021)
KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia
eLife 10:e57436.
https://doi.org/10.7554/eLife.57436

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