Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, 12801 E 17th Ave., Aurora, CO 80045, USA.
Mol Cancer Res. 2010 Dec;8(12):1643-55. doi: 10.1158/1541-7786.MCR-10-0111. Epub 2010 Nov 2.
HOX (homeobox) genes encode homeodomain-containing transcription factors critical to development, differentiation, and homeostasis. Their dysregulation has been implicated in a variety of cancers. Previously, we showed that a subset of genes of the HOXC cluster is upregulated in primary prostate tumors, lymph node metastases, and malignant prostate cell lines. In the present study, we show that HOXC8 inhibits androgen receptor (AR)-mediated gene induction in LNCaP prostate cancer cells and HPr-1 AR, a nontumorigenic prostate epithelial cell line. Mechanistically, HOXC8 blocks the AR-dependent recruitment of the steroid receptor coactivators steroid receptor coactivator-3 (SRC-3), and CREB binding protein to the androgen-regulated prostate-specific antigen gene enhancer and inhibits histone acetylation of androgen-regulated genes. Inhibition of androgen induction by HOXC8 is reversed upon expression of SRC-3, a member of the SRC/p160 steroid receptor cofactor family. Coimmunoprecipitation studies show that HOXC8 expression inhibits the hormone-dependent interaction of AR and SRC-3. Finally, HOXC8 expression increases invasion in HPr-1 AR nontumorigenic cells. These data suggest a complex role for HOXC8 in prostate cancer, promoting invasiveness while inhibiting AR-mediated gene induction at androgen response element-regulated genes associated with differentiated function of the prostate. A greater understanding of HOXC8 actions in the prostate and its interactions with androgen signaling pathways may elucidate mechanisms driving the onset and progression of prostate cancer.
HOX（同源盒）基因编码含有同源结构域的转录因子，对发育、分化和内稳态至关重要。它们的失调与多种癌症有关。以前，我们表明 HOXC 簇的一组基因在原发性前列腺肿瘤、淋巴结转移和恶性前列腺细胞系中上调。在本研究中，我们表明 HOXC8 抑制雄激素受体 (AR) 在 LNCaP 前列腺癌细胞和 HPr-1 AR（一种非致瘤性前列腺上皮细胞系）中的基因诱导。从机制上讲，HOXC8 阻止 AR 依赖性募集甾体受体共激活因子甾体受体共激活因子-3 (SRC-3) 和 CREB 结合蛋白到雄激素调节的前列腺特异性抗原基因增强子，并抑制雄激素调节基因的组蛋白乙酰化。HOXC8 对雄激素诱导的抑制作用在 SRC-3 表达后逆转，SRC-3 是 SRC/p160 甾体受体共激活因子家族的成员。共免疫沉淀研究表明，HOXC8 表达抑制 AR 和 SRC-3 的激素依赖性相互作用。最后，HOXC8 表达增加了 HPr-1 AR 非致瘤细胞的侵袭性。这些数据表明 HOXC8 在前列腺癌中具有复杂的作用，促进侵袭性，同时抑制与前列腺分化功能相关的雄激素反应元件调节基因的 AR 介导的基因诱导。对 HOXC8 在前列腺中的作用及其与雄激素信号通路的相互作用的更深入了解可能阐明驱动前列腺癌发生和进展的机制。
