KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia
- University of Pennsylvania, United States
- 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.
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HIF1α enrichment on KSHV genome in normoxia and hypoxiaNCBI Gene Expression Omnibus, GSE149401.
Article and author information
Author details
Rajnish Kumar singh
Zachary L Lamplugh
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
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
Version history
- Received: March 31, 2020
- Preprint posted: August 12, 2020 (view preprint)
- Accepted: July 17, 2021
- Accepted Manuscript published: July 19, 2021 (version 1)
- 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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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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