Hypoxia drives transient site-specific copy gain and drug-resistant gene expression
- Joshua C. Black1,7,
- Elnaz Atabakhsh1,7,
- Jaegil Kim2,7,
- Kelly M. Biette1,
- Capucine Van Rechem1,
- Brendon Ladd1,
- Paul d. Burrowes1,
- Carlos Donado1,
- Hamid Mattoo1,
- Benjamin P. Kleinstiver3,4,
- Bing Song1,
- Grasiella Andriani5,
- J. Keith Joung3,4,
- Othon Iliopoulos1,6,
- Cristina Montagna5,
- Shiv Pillai1,
- Gad Getz2,3 and
- Johnathan R. Whetstine1
- 1Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
- 2Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;
- 3Massachusetts General Hospital Cancer Center, Department of Pathology, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
- 4Massachusetts General Hospital Center for Computational and Integrative Biology, Charlestown, Massachusetts 02129, USA;
- 5Department of Genetics, Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, USA;
- 6Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- Corresponding author: jwhetstine{at}hms.harvard.edu
-
↵7 These authors contributed equally to this work.
Abstract
Copy number heterogeneity is a prominent feature within tumors. The molecular basis for this heterogeneity remains poorly characterized. Here, we demonstrate that hypoxia induces transient site-specific copy gains (TSSGs) in primary, nontransformed, and transformed human cells. Hypoxia-driven copy gains are not dependent on HIF1α or HIF2α; however, they are dependent on the KDM4A histone demethylase and are blocked by inhibition of KDM4A with a small molecule or the natural metabolite succinate. Furthermore, this response is conserved at a syntenic region in zebrafish cells. Regions with site-specific copy gain are also enriched for amplifications in hypoxic primary tumors. These tumors exhibited amplification and overexpression of the drug resistance gene CKS1B, which we recapitulated in hypoxic breast cancer cells. Our results demonstrate that hypoxia provides a biological stimulus to create transient site-specific copy alterations that could result in heterogeneity within tumors and cell populations. These findings have major implications in our understanding of copy number heterogeneity and the emergence of drug resistance genes in cancer.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.259796.115.
-
Freely available online through the Genes & Development Open Access option.
- Received February 6, 2015.
- Accepted April 20, 2015.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.