Journal
GENES & DEVELOPMENT
Volume 29, Issue 10, Pages 1018-1031Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.259796.115
Keywords
CNV; JmjC; KDM4A; hypoxia; site-specific copy gain; tumor heterogeneity
Categories
Funding
- American Cancer Society [RSG-13-115-01-CCG, CA059267, R01GM097360]
- American Lung Association Lung Cancer Discovery Award
- National Institutes of Health [U24CA143845]
- Massachusetts General Hospital Executive Committee on Research (ECOR) Tosteson Post-doctoral Fellowship
- Senior Research Training Fellowship from the American Lung Association
- Fund for Medical Discovery
- Marsha Rivkin Center for Ovarian Cancer Research
- National Sciences and Engineering Research Council of Canada
- National Institutes of Health Director's Pioneer Award [DP1 GM105378]
- Jim and Ann Orr Research Scholar Award
- AbbVie
- Canada Foundation for Innovation (CFI)
- Canadian Institutes of Health Research (CIHR)
- Genome Canada
- Ontario Genomics Institute [OGI-055]
- GlaxoSmithKline
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Structural Genomics Consortium
- Jane Coffin Childs Memorial Fund for Medical Research
- Boehringer Ingelheim
- Janssen
- Lilly Canada
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- [1RO1CA160458]
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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 HIF1 alpha or HIF2 alpha; 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.
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