Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival
Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival
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DOI：
10.1128/mcb.05958-11
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Cheung, Edwin
中科院分区：
文献类型：
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作者：
Tan, Peck Yean;Chang, Cheng Wei;Cheung, Edwin
NKX3-1基因是前列腺癌进展所必需的同源框基因，但它的功能尚不清楚。在这里，使用染色质免疫沉淀结合大规模平行测序(CHIP-SEQ)，我们发现NKX3-1与前列腺癌基因组中的雄激素受体(AR)共定位。我们揭示了NKX3-1控制前列腺癌AR转录网络的两种不同机制。首先，NKX3-1和AR在前馈调节环路中直接相互调节。其次，NKX3-1与AR和FoxA1协同调节晚期和复发前列腺癌的基因。NKX3-1和AR共同调节的基因包括那些在整合致癌信号通路的“蛋白质运输”过程中发现的基因。此外，我们证明了NKX3-1、AR和FoxA1通过直接上调RAB GTPase家族的成员RAB3B来促进前列腺癌细胞的存活。最后，我们发现RAB3B在前列腺癌患者中过表达，这表明RAB3B与AR、FoxA1和NKX3-1一起是前列腺癌进展的重要调节因子。总之，我们的工作突出了NKX3-1、AR和RAB GTPase信号通路之间的一个新的分层转录调控网络，该信号通路对于雄激素依赖型前列腺癌的遗传-分子-表型范式至关重要。
The NKX3-1 gene is a homeobox gene required for prostate tumor progression, but how it functions is unclear. Here, using chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) we showed that NKX3-1 colocalizes with the androgen receptor (AR) across the prostate cancer genome. We uncovered two distinct mechanisms by which NKX3-1 controls the AR transcriptional network in prostate cancer. First, NKX3-1 and AR directly regulate each other in a feed-forward regulatory loop. Second, NKX3-1 collaborates with AR and FoxA1 to mediate genes in advanced and recurrent prostate carcinoma. NKX3-1- and AR-coregulated genes include those found in the "protein trafficking" process, which integrates oncogenic signaling pathways. Moreover, we demonstrate that NKX3-1, AR, and FoxA1 promote prostate cancer cell survival by directly upregulating RAB3B, a member of the RAB GTPase family. Finally, we show that RAB3B is overexpressed in prostate cancer patients, suggesting that RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlights a novel hierarchical transcriptional regulatory network between NKX3-1, AR, and the RAB GTPase signaling pathway that is critical for the genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.