Regulation of transient site-specific copy gain by MicroRNA

Joshua C. Black, Hailei Zhang, Jaegil Kim, Gad Getz, Johnathan R. Whetstine

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish
Pages (from-to)4862-4871
Number of pages10
JournalJournal of Biological Chemistry
Issue number10
StatePublished - Mar 4 2016
Externally publishedYes


  • Breast Neoplasms/genetics
  • CDC2-CDC28 Kinases/genetics
  • Cell Line, Tumor
  • Female
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Jumonji Domain-Containing Histone Demethylases/genetics
  • MicroRNAs/genetics


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