title: 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.affiliation: From the Drug Discovery Department, Moffitt Cancer Center, and the Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, Florida 33612 kiran.mahajan@moffitt.org.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mahajan
authors.affiliation: From the Drug Discovery Department, Moffitt Cancer Center, and the Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, Florida 33612.
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.affiliation: From the Drug Discovery Department, Moffitt Cancer Center, and the Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, Florida 33612.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.affiliation: From the Drug Discovery Department, Moffitt Cancer Center, and the Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, Florida 33612 nupam.mahajan@moffitt.org.
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000069439:Dasatinib; D056484:Jumonji Domain-Containing Histone Demethylases; D008156:Luciferases; D020890:Neuregulin-1; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D013844:Thiazoles; C476420:NOXA1 protein, human; C094131:NRG1 protein, human; C530247:KDM3A protein, human; C508053:ERBB2 protein, human; C403262:TNK2 protein, human
keywords: Breast Cancer; Cancer Therapy; Oncogene; Signal Transduction; Transcription Regulation; Tyrosine-Protein Kinase (Protein-tyrosine Kinase)