Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 10, Pages 4862-4871Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.711648
Keywords
chromatin; drug resistance; genomic instability; histone demethylase; microRNA (miRNA); CKS1B; JMJD2A; KDM4A; TSSG; cisplatin
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Funding
- American Cancer Society Grant [RSG-13-115-01-CCG]
- National Institutes of Health Grants [CA059267, R01GM097360, U24CA143845]
- Jane Coffin Childs Memorial Fund
- Massachusetts General Hospital Executive Committee on Research Tosteson Postdoctoral Fellowship
- American Lung Association Lung Cancer Discovery Award
- Alex Lemonade Stand Foundation
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Intra-tumor copy number heterogeneity is commonly observed in cancer; however, the molecular mechanisms that contribute to heterogeneity remain poorly understood. Up-regulation of the histone demethylase KDM4A promotes transient site-specific copy gain (TSSG) in cells; therefore, uncovering how KDM4A levels are controlled is important for understanding the regulation of copy number heterogeneity. Here, we demonstrate that KDM4A is regulated by hsa-mir-23a-3p, hsa-mir-23b-3p, and hsa-mir-137. Altering expression of these microRNAs (miRNAs) regulates KDM4A-dependent TSSG. miRNA inhibition promoted copy gains and increased expression of the drug-resistant oncogene CKS1B, which was further substantiated in primary breast tumors. Consistent with increased CKS1B expression, miRNA inhibition reduced breast cancer cell sensitivity to cisplatin. Our data identify these miRNAs as regulators of TSSG and copy gains of a drug resistance gene.
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