title: Hypoxia drives transient site-specific copy gain and drug-resistant gene expression.
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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Elnaz
authors.initials: E
authors.lastname: Atabakhsh
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Biette
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Paul D
authors.initials: PD
authors.lastname: Burrowes
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Carlos
authors.initials: C
authors.lastname: Donado
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Pathology, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Massachusetts General Hospital Center for Computational and Integrative Biology, Charlestown, Massachusetts 02129, USA;
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Kleinstiver
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Bing
authors.initials: B
authors.lastname: Song
authors.affiliation: Department of Genetics, Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, USA;
authors.forename: Grasiella
authors.initials: G
authors.lastname: Andriani
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Pathology, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Massachusetts General Hospital Center for Computational and Integrative Biology, Charlestown, Massachusetts 02129, USA;
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA; Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Othon
authors.initials: O
authors.lastname: Iliopoulos
authors.affiliation: Department of Genetics, Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, USA;
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA; Massachusetts General Hospital Cancer Center, Department of Pathology, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA; jwhetstine@hms.harvard.edu.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D056915:DNA Copy Number Variations / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D015027:Zebrafish
chemical_list: C093090:CKS1B protein, human; D042846:CDC2-CDC28 Kinases
keywords: CNV; JmjC; KDM4A; hypoxia; site-specific copy gain; tumor heterogeneity