An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer

作者：Chen, Changhao; Cai, Qingqing; He, Wang; Li, Zhihua; Zhou, Fangjian; Liu, Zhuowei; Zhong, Guangzheng; Chen, Xu; Zhao, Yue; Dong, Wen; Huang, Jian; Zheng, Jianping; Lin, Tianxin^*

来源：International Journal of Cancer, 2016, 138(1): 74-86.

DOI：10.1002/ijc.29677

• prostate cancer
• single nucleotide polymorphism
• L-plastin
• NKX3
• 1
• molecular regulation

The L-plastin gene is involved in the invasion and metastasis of prostate cancer. However, the molecular mechanisms underlying L-plastin transcription are unclear. We hypothesize that the occurrence of polymorphic genetic variations in the L-plastin promoter might affect an individual's susceptibility to prostate cancer. In this study, we identified a single nucleotide polymorphism (SNP) at position -1,687 in the L-plastin promoter by genotype sequencing. The SNP -1,687 showed different transcriptional activity in the luciferase assay in vitro. The TRANSFAC software was applied to predict the multiple cis-elements, and luciferase assay was used to further identify the L-plastin regulatory region. We performed EMSAs, supershift assays and ChIP-qPCR demonstrated that the transcriptional suppressor NKX3.1 binds to the SNP site of the L-plastin promoter. SNP -1,687 (T/T) led to an increase in the affinity of NKX3.1 for L-plastin promoter, resulted in lower levels of L-plastin RNA and protein expression. Furthermore, we collected and sequenced samples from 640 individuals (372 prostate cancer patients and 268 healthy controls) from 2000 to 2013. The results showed that SNP -1,687 (T/T) occurred more frequently in the healthy individuals than that in the prostate cancer patients compared to SNP -1,687 (C/C). Similarly, SNP -1,687 (T/T) genotype occurred more frequently compared to SNP -1,687 (C/C) genotype in the patients with low and moderately differentiated tumors. In conclusion, SNP -1,687, located in the NKX3.1 binding site within the L-plastin promoter, might reduce the expression of L-plastin and potentially decrease the tumorigenesis and progression of prostate cancer. This SNP could be a potential prognostic factor for prostate cancer. @@@ What's new? A single base pair change in a gene's promoter region can influence cancer progression, according to new results. The L-plastin gene is important for prostate cancer invasion and metastasis, and these authors sequenced the promoter region looking for variable regions. They identified a SNP at position-1687; then they showed that a transcriptional suppressor binds this site. One of the variant sequences helps that suppressor bind more strongly, and that variant showed up more often in healthy individuals and low recurrence risk in those with cancer. Thus, this L-plastin promoter SNP could be a useful indicator for prostate cancer prognosis.

• 出版日期2016-1-1
• 单位中山大学