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

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

doi:10.1002/ijc.29677

Cited by 13 publications

(7 citation statements)

References 37 publications

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“…We have previously demonstrated that L -plastin is a potential biomarker for PCa progression. 15 , 21 To determine whether L -plastin functions in CRPC progression, we established an androgen-independent LNCaP subline known as LNCaP-AI using previously described methods. 22 , 23 , 24 LNCaP cells have an epithelial morphology and feature tapered unbranched processes; LNCaP-AI cells exhibit a neuronal morphology with compactly rounded cell bodies ( Figure 1a ).…”

Section: Resultsmentioning

confidence: 99%

AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin

et al. 2017

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The transition from androgen-dependent to metastatic castration-resistant prostate cancer (PCa) is a lethal event of uncertain molecular aetiology. Our previous studies demonstrated that L-plastin is involved in PCa invasion and metastasis and is upregulated by androgen and oestrogen in the hormone-dependent PCa cell line LNCaP. We recently found that L-plastin expression is consistently activated even after androgen deprivation, suggesting that androgen-independent transcription factors may regulate its expression. Herein, we performed sequential deletion and luciferase analysis of the L-plastin promoter and found that an androgen-independent regulatory factor prominently located in the region close to the transcription initiation site (−216 to +118) may facilitate L-plastin upregulation. AP4 was then identified as the relevant transcription activator that directly binds to the L-plastin promoter, as confirmed by EMSAs, supershift assays and CHIP-qPCR experiments. Moreover, we determined that the AP4/L-plastin axis is regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, contributing to PCa metastasis and castration resistance. Furthermore, we found that AP4 promotes PCa metastasis by upregulating L-plastin expression in vitro and in vivo. We collected a total of 136 PCa tissues and corresponding adjacent normal tissues from patients who underwent prostatectomy at Sun Yat-Sen Memorial Hospital from 2005 to 2015 and measured AP4 and L-plastin protein levels by immunohistochemistry. The results showed that AP4 levels strongly correlated with those of its downstream target gene L-plastin, were significantly upregulated in PCa tissues, were positively correlated with lymph node metastasis and Gleason scores over 7, and were an independent prognostic factor for patient survival. In summary, these findings support a plausible mechanism by which the AP4/L-plastin axis is regulated by the PI3K/AKT pathway in human PCa and may represent a novel therapeutic target in PCa treatment.

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Section: Resultsmentioning

confidence: 99%

AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin

et al. 2017

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“…Numerous studies have revealed that promoter variants can cause significantly potential phenotype diversity, and most of the regulatory mechanisms are associated with the change of transcription factor binding and promoter activity 35 . For example, a single mutation at position −1,687 in human L-plastin gene affected the binding strength of the transcriptional suppressor NKX3.1, and further reduced the expression of L-plastin and potentially decreased the tumorigenesis and progression of prostate cancer 36 . Dominquez et al .…”

Section: Discussionmentioning

confidence: 99%

A novel PAX7 10-bp indel variant modulates promoter activity, gene expression and contributes to different phenotypes of Chinese cattle

Shi

Zhou

et al. 2018

Sci Rep

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Paired box 7 (PAX7) gene regulates the conversion of muscle satellite cells into myogenic cells and participates in multi-step processes in myogenesis.Expression levels of PAX7 are decisive for its regulatory function. Previous reports revealed that PAX7 were responsible for the developmental traits of muscle. The relationship of the PAX7 promoter variants and livestock phenotypic traits has not been fully elucidated. We detected a novel 10-bp insertion/deletion (indel) polymorphism in the bovine PAX7 promoter and revealed that the indel altered the binding of the transcriptional factor ZNF219. Luciferase reporter assay showed that deletion-deletion (Del-Del) genotype of the PAX7 gene showed 2.79-fold higher promoter activity than the insertion-insertion (Ins-Ins) genotype (P < 0.05), and ZNF219 overexpression significantly diminished the luciferase activity in Ins-Ins groups. Moreover, the expression of PAX7 and its down-stream genes were detected in fetal skeletal muscle of cattle with different PAX7 genotypes, where the Del-Del genotype also displayed high expression levels. Statistical association analysis demonstrated that this indel had significant effects on early growth traits in cattle. These findings provide a complete overview of the function of the PAX7 10-bp variant, which may have potential as a genetic marker for marker-assisted selection in improving economically significant traits of cattle.Cattle phenotypes of economic significance, such as growth rates, carcass, and meat quality, have attracted much attention from breeders in the beef cattle industry. Such phenotypes constitute a multifactorial background that arises from interactions between environmental and genetic factors 1 . In marker-assisted selection programs, the efficiency of selection is associated with the identification of candidate genes, as well as the exploration of genome-wide variation markers that are responsible for the complex quantitative traits 2 . The establishment of genetic association approach provides a unique opportunity to study genotype-phenotype relationships 3 . Therefore, the integration of screening for variations and gene association programs can improve assessments of the genetic effects of candidate genes, thus providing promising materials for successful genetic selection in cattle breeding.Muscle satellite cells, known as muscle-specific committed progenitors, are located under the basal lamina of muscle fibres and play important roles in the growth, maintenance, homeostasis, repair, and regeneration of skeletal muscle [4][5][6] . Paired box 7 (PAX7) gene, a member of the paired box gene family, is the marker gene of myogenic satellite cells 7 . PAX7 is specifically expressed in quiescent, activated, and proliferating satellite cells, and PAX7-expressing satellite cells are indispensable for the postnatal muscle development and regeneration after the injury of skeletal muscle, however, their regenerative function can not be performed by other endogenous cell

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“…Although little is known about the molecular mechanisms that regulate LCP1 transcription and translation, a variant in the promoter region of LCP1 causes a decreased risk for prostrate cancer (Chen et al 2016) while other variants in LCP1 are proposed as biomarkers for colorectal cancer recurrence and eQTLs (Garge et al 2010;Ning et al 2014). We performed probing experiments on LCP1 to determine how the presence of proteins affects structural ensemble and how dependent LCP1 structure is upon cellular conditions.…”

Section: Structured Coding Region Of Lcp1 Mrnamentioning

confidence: 99%

Allele-specific SHAPE-MaP assessment of the effects of somatic variation and protein binding on mRNA structure

Lackey

Coria

Woods

et al. 2018

RNA

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The precise impact of inherited and somatic mutations on messenger RNA (mRNA) structure remains poorly understood. Recent technological advances that leverage next generation sequencing to obtain experimental structure data, such as SHAPE-MaP (Selective 2' Hydroxyl Acylation by Primer Extension and Mutational Profiling), can reveal structural effects of mutations especially when this data is rigorously incorporated in RNA structural modeling. Here we analyze the ability of SHAPE-MaP to detect the relatively subtle structural changes caused by single nucleotide mutations. We find that allele-specific sorting greatly improved the detection ability of SHAPE-MaP. Thus, we used SHAPE-MaP with a novel combination of clone-free robotic mutagenesis and allele-specific sorting to perform a rapid, comprehensive survey of non-coding somatic and inherited riboSNitches in two cancer-associated mRNAs, TPT1 and LCP1. Combined with rigorous thermodynamic modeling of the Boltzmann suboptimal ensemble we identified a subset of somatic and Lackey 2 inherited mutations that change TPT1 and LCP1 RNA structure, with approximately 14% of all variants identified acting as riboSNitches. To confirm that these in vitro structures were biologically relevant, we tested how dependent TPT1 and LCP1 mRNA structures are on their environments. We performed SHAPE-MaP on TPT1 and LCP1 mRNAs in the presence or absence of cellular proteins and found that both TPT1 and LCP1 have similar overall folds in all conditions. RiboSNitches identified within these mRNAs in vitro are likely to exist under biological conditions. Overall, these data reveal a remarkably robust mRNA structural landscape where differences in environmental conditions and most sequence variants do not significantly alter RNA structural ensembles. Finally, predicting riboSNitches in mRNAs from sequence alone remains particularly challenging; these data will provide the community with a benchmark for further algorithmic development.

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

Cited by 13 publications

References 37 publications

AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin

AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin

A novel PAX7 10-bp indel variant modulates promoter activity, gene expression and contributes to different phenotypes of Chinese cattle

Allele-specific SHAPE-MaP assessment of the effects of somatic variation and protein binding on mRNA structure

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