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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.
Highlights
Cancer is often characterized by copy gains or losses of chromosome arms, whole chromosomes, and/or amplifications/deletions of smaller genomic fragments (Hook et al 2007; Stratton et al 2009; Beroukhim et al 2010)
These results suggest that hypoxia can promote site-specific copy gain and increased expression of drug resistance genes such as CDC28 protein kinase regulatory subunit 1B (CKS1B)
Analysis of 1q12h and 1q21.2 in the same cells revealed that the gains in hypoxic conditions were predominantly mutually exclusive (Fig. 1C), which further underscored the site-specific nature of the gains. These results suggest that hypoxia promotes site-specific copy gain
Summary
Cancer is often characterized by copy gains or losses of chromosome arms, whole chromosomes, and/or amplifications/deletions of smaller genomic fragments (Hook et al 2007; Stratton et al 2009; Beroukhim et al 2010). Pretreatment of cells with succinate (a naturally occurring metabolite that inactivates α-ketoglutaratedependent enzymes) or a lysine demethylase (KDM) chemical inhibitor blocks hypoxia-induced gains These observations highlight the dynamics associated with copy gain and suggest that enzyme levels, S-phase status, cellular stresses, and metabolic state could contribute to the copy number heterogeneity observed in human tumors. These results suggest that hypoxia can promote site-specific copy gain and increased expression of drug resistance genes such as CKS1B These data uncover a mechanism that could account for both copy number and expression heterogeneity observed in solid tumors and establish a molecular basis for drug resistance gene selection (Patel et al 2014)
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