近日,，來自范德比爾特英格拉姆癌癥中心的研究者通過研究揭示了兩種蛋白扮演的角色完全相反,，一種蛋白質可以促進癌癥發(fā)生,，另外一種可以抑制癌癥發(fā)生，然而在前列腺癌中,，這兩種蛋白質可以調節(jié)相同的一系列基因表達,。相關研究成果刊登在了近日的國際雜志Journal of Clinical Investigation上。
研究者使用小鼠模型來研究涉及前列腺癌的分子路徑,，研究者Anderson使用基因組學技術來理解缺失腫瘤抑制蛋白NKX3.1如何促進前列腺癌的發(fā)生,。NKX3.1是一個轉錄調節(jié)子,，其可以結合至某些基因上影響這些基因的表達。這個基因就是在人類前列腺癌中常見的缺失基因。Anderson分離了NKX3.1的蛋白質,，并且鑒定出了9817個基因可以與蛋白質結合,，其中282個基因可以受NKX3.1蛋白質來調節(jié)，當NKX3.1缺失后,，這些基因就會異常表達,。
使用生物信息學工具,，研究者發(fā)現(xiàn)了NKX3.1調節(jié)基因的四分之一都可以被抑癌基因Myc來結合,。以前的研究結果證實在前列腺癌中，NKX3.1的水平下降,，而Myc的水平上升,。
研究者構建了前列腺癌小鼠模型，然而,，僅僅缺少NKX3.1的小鼠可以發(fā)展為早期前列腺癌，但是疾病不會繼續(xù)惡化,。研究者預測,，另外一種遺傳突變或許對癌癥的發(fā)展至關重要。當然了Myc就是其中很有可能的一個機制,。
因此研究者McKissic構建了NKX3.1缺失，但是Myc高表達的前列腺癌小鼠模型,，發(fā)現(xiàn)這種小鼠可以發(fā)展為晚期前列腺癌,。
為了研究其臨床關聯(lián)性,，研究者分析了來自前列腺癌病人的遺傳和臨床數(shù)據(jù)，發(fā)現(xiàn)這些靶位基因的高表達和腫瘤的復發(fā)惡化直接相關,，尤其是一些靶位基因的抑制或許可以預測腫瘤的惡化程度,。后續(xù)研究者們會繼續(xù)深入研究來闡明其具體的機制。（生物谷Bioon.com）
編譯自：Proteins May Point Way to New Prostate Cancer Drug Targets
doi:10.1172/JCI58540
PMC:
PMID:
Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis
Philip D. Anderson1, Sydika A. McKissic1, Monica Logan2, Meejeon Roh1, Omar E. Franco3, Jie Wang1, Irina Doubinskaia1, Riet van der Meer1, Simon W. Hayward3,4, Christine M. Eischen1,4, Isam-Eldin Eltoum5 and Sarki A. Abdulkadir1,4
Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.
