ACK1 tyrosine kinase interacts with histone demethylase KDM3A to regulate the mammary tumor oncogene HOXA1.

Abstract

Hormone therapy with the selective estrogen-receptor modulator tamoxifen provides a temporary relief for patients with estrogen receptor α (ER)-positive breast cancers. However, a subset of patients exhibiting overexpression of the HER2 receptor tyrosine kinase displays intrinsic resistance to tamoxifen therapy. Therefore, elucidating the mechanisms promoting the estrogen (E2)-independent ER-regulated gene transcription in tamoxifen-resistant breast tumors is essential to identify new therapeutic avenues to overcome drug resistance and ameliorate poor prognosis. The non-receptor tyrosine kinase, ACK1 (also known as TNK2), has emerged as a major integrator of signaling from various receptor tyrosine kinases including HER2. We have uncovered that heregulin-mediated ACK1 activation promoted ER activity in the presence of tamoxifen, which was significantly down-regulated upon ACK1 knockdown or inhibition of ACK1 by small molecule inhibitors, AIM-100 or Dasatinib. We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen. Consistent with this finding, ACK1 activation resulted in a significant decrease in the deposition of dimethyl H3K9 epigenetic marks. Conversely, inhibition of ACK1 by AIM-100 or Dasatinib restored dimethyl H3K9 methylation marks and caused transcriptional suppression of the ER-regulated gene HOXA1. Thus, by its ability to regulate the epigenetic activity of an ER co-activator KDM3A, ACK1 modulates HOXA1 expression in the absence of E2, conferring tamoxifen resistance. These data reveal a novel therapeutic option, suppression of ACK1 signaling by AIM-100 or Dasatinib, to mitigate HOXA1 up-regulation in breast cancer patients displaying tamoxifen resistance.

• Authors: Kiran Mahajan, Harshani R Lawrence, Nicholas J Lawrence, Nupam P Mahajan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 41 Pg. 28179-91 (Oct 10 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25148682 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport
• NOXA1 protein, human
• NRG1 protein, human
• Neuregulin-1
• Pyrimidines
• Thiazoles
• Tamoxifen
• Luciferases
• Jumonji Domain-Containing Histone Demethylases
• KDM3A protein, human
• ERBB2 protein, human
• Protein-Tyrosine Kinases
• Receptor, ErbB-2
• TNK2 protein, human
• Dasatinib

Topics

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport (genetics, metabolism)
• Amino Acid Sequence
• Animals
• Binding Sites
• Cell Line, Tumor
• Dasatinib
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Humans
• Jumonji Domain-Containing Histone Demethylases (genetics, metabolism)
• Luciferases (genetics, metabolism)
• Mammary Glands, Human (drug effects, metabolism, pathology)
• Methylation
• Models, Molecular
• Molecular Sequence Data
• Neuregulin-1 (genetics, metabolism)
• Protein Binding
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Receptor, ErbB-2 (genetics, metabolism)
• Signal Transduction
• Tamoxifen (pharmacology)
• Thiazoles (pharmacology)
• Transcription, Genetic