RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression.
RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression.
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DOI：
10.1158/0008-5472.can-17-0669
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发表时间：
2017-08-15
期刊：
影响因子：
11.2
通讯作者：
Ittmann M
中科院分区：
文献类型：
--
作者：
Wang Y;Wang J;Zhang L;Karatas OF;Shao L;Zhang Y;Castro P;Creighton CJ;Ittmann M
非洲裔美国人（AA）男性表现出相对较高的发病率和死亡率，由于前列腺癌（PCa），即使调整后的社会经济因素，但这种差异的生物学基础尚不清楚。在这里，我们确定了一个新的区域染色体4p16.3是选择性地在AA PCa丢失。G蛋白信号转导的负调节因子RGS12被定义为4p16.3缺失的靶点，尽管它以前没有被认为是肿瘤抑制基因。RGS12转录水平在AA PCa中相对降低，并且PCa细胞系相对于良性前列腺上皮细胞显示降低的RGS12表达。值得注意的是，RGS12在体外和体内的PCa和前列腺上皮细胞系中表现出有效的肿瘤抑制活性。我们发现RGS12的表达与癌基因MNX1呈负相关，并在体外和体内调节其表达。此外，MNX1受AKT活性调节，RGS12表达降低总AKT水平和活化AKT水平。我们的研究结果确定RGS12是AA PCa中的候选肿瘤抑制基因，其通过降低AKT和MNX1的表达起作用，在这种不同的疾病背景中建立新的致癌轴。
African American (AA) men exhibit a relatively high incidence and mortality due to prostate cancer (PCa) even after adjustment for socioeconomic factors, but the biological basis for this disparity is unclear. Here we identify a novel region on chromosome 4p16.3 that is lost selectively in AA PCa. The negative regulator of G-protein signaling RGS12 was defined as the target of 4p16.3 deletions, although it has not been implicated previously as a tumor suppressor gene. RGS12 transcript levels were relatively reduced in AA PCa and PCa cell lines showed decreased RGS12 expression relative to benign prostate epithelial cells. Notably, RGS12 exhibited potent tumor suppressor activity in PCa and prostate epithelial cell lines in vitro and in vivo. We found that RGS12 expression correlated negatively with the oncogene MNX1 and regulated its expression in vitro and in vivo. Further, MNX1 was regulated by AKT activity and RGS12 expression decreased total and activated AKT levels. Our findings identify RGS12 is a candidate tumor suppressor gene in AA PCa which acts by decreasing expression of AKT and MNX1, establishing a novel oncogenic axis in this disparate disease setting.