ACK1 Tyrosine Kinase Interacts with Histone Demethylase KDM3A to Regulate the Mammary Tumor Oncogene HOXA1
ACK1 Tyrosine Kinase Interacts with Histone Demethylase KDM3A to Regulate the Mammary Tumor Oncogene HOXA1
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DOI：
10.1074/jbc.m114.584425
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发表时间：
2014-10-10
影响因子：
4.8
通讯作者：
Mahajan, Nupam P.
中科院分区：
文献类型：
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作者：
Mahajan, Kiran;Lawrence, Harshani R.;Mahajan, Nupam P.
使用选择性雌激素受体调节剂他莫昔芬进行激素治疗可以暂时缓解雌激素受体 α (ER) 阳性乳腺癌患者的症状。然而，一部分 HER2 受体酪氨酸激酶过度表达的患者对他莫昔芬治疗表现出内在耐药性。因此，阐明在他莫昔芬耐药性乳腺肿瘤中促进不依赖于雌激素（E-2）的 ER 调节基因转录的机制对于确定克服耐药性和改善不良预后的新治疗途径至关重要。非受体酪氨酸激酶 ACK1（也称为 TNK2）已成为包括 HER2 在内的各种受体酪氨酸激酶信号传导的主要整合者。我们发现，在他莫昔芬存在的情况下，heregulin 介导的 ACK1 激活可促进 ER 活性，而当 ACK1 敲低或小分子抑制剂 AIM-100 或达沙替尼抑制 ACK1 时，ER 活性显着下调。我们报告说，即使在他莫昔芬存在的情况下，ACK1也会以调蛋白依赖的方式在进化保守的酪氨酸1114位点磷酸化ER共激活剂KDM3A（一种H3K9去甲基酶）。与这一发现一致的是，ACK1 激活导致二甲基 H3K9 表观遗传标记的沉积显着减少。相反，AIM-100 或达沙替尼抑制 ACK1 可恢复二甲基 H3K9 甲基化标记，并导致 ER 调节基因 HOXA1 的转录抑制。因此，通过其调节 ER 共激活因子 KDM3A 的表观遗传活性的能力，ACK1 在 E-2 不存在的情况下调节 HOXA1 表达，从而赋予他莫昔芬耐药性。这些数据揭示了一种新的治疗选择，即通过 AIM-100 或达沙替尼抑制 ACK1 信号传导，以减轻显示他莫昔芬耐药的乳腺癌患者中 HOXA1 的上调。
Hormone therapy with the selective estrogen-receptor modulator tamoxifen provides a temporary relief for patients with estrogen receptor alpha (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 (E-2)-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 E-2, 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.