Abstract
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.
Highlights
Tics often harbor chromosome 1q12-25 cytogenetic gains; the genes that contribute to this phenotype may vary depending on tumor type even though the same cytogenetic region is gained [2,3,4,5,6,7,8,9,10]
KDM4A Is Regulated by miRNAs—KDM4A is an important regulator of transient site-specific copy gains (TSSGs) [11,12,13,14]
Our results demonstrate that miRNAs can impact copy number heterogeneity through the regulation of TSSGs by directly regulating a chromatin-modifying enzyme
Summary
KDM4A 3Ј-UTR to luciferase rendered it responsive to these miRNAs, which was blocked by mutation of the hsa-mir-23a/b and hsa-mir-137 seed sequences. Treatment with hsa-mir-23a/b or hsa-mir-137 mimics was sufficient to abrogate KDM4A-dependent TSSGs in response to hypoxia Consistent with these observations, we used miRNA inhibitors in MDA-MB-231 breast cancer cells to promote gain of 1q12-21 as well as the amplification and increased expression of CKS1B, which is a drug-resistant oncogene (4, 20 –23). Analysis of primary breast tumors (BRCA) in The Cancer Genome Atlas (TCGA) revealed that deletion of hsa-mir-23a correlates with increased copy number of 1q12-21 in primary tumors and associates with copy gain and increased expression of the drugresistant oncogene CKS1B. Consistent with these observations, miRNA inhibitors reduced breast cancer cell response to cisplatin. Our results implicate miRNA regulation as a modulator of TSSGs and suggest that miRNA therapy could be used to reduce KDM4A-driven copy number heterogeneity and potentially affect drug resistance
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