Shi G, Wang Y, Zhang C, et al.
Identification of genes involved in the four stages of colorectal cancer: Gene expression profiling.Mol Cell Probes. 2018; 37:39-47 [
PubMed]
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BACKGROUND: Colorectal cancer (CRC) is a common cancer with high morbidity and mortality. However, its molecular mechanism is not clear, nor the genes related to CRC stages.
METHODS: Gene expression data in CRC and healthy colorectal tissues were obtained from gene expression omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between control and CRC (stage I, II, III, and IV), obtaining 4 DEG sets. VennPlex was utilized to find all DEGs and intersection DEGs. Functional interactions between all DEGs and protein-protein interactions (PPIs) between intersection DEGs were analyzed using ReactomeFIViz and STRING, respectively, and networks were visualized. Known CRC-related genes were down-loaded from Comparative Toxicogenomics Database and mapped to PPI network.
RESULTS: Totally, 851, 760, 729, and 878 DEGs were found between control and CRC stage I, II, III, and IV, respectively. Taken together, 1235 DEGs were found, as well as 128 up-regulated intersection DEGs, 365 down-regulated intersection DEGs, and 0 contra-regulated DEG. A functional interaction network of all DEGs and a PPI network of intersection DEGs were constructed, in which CDC20, PTTG1, and MAD2L1 interacted with BUB1B; UGT2B17 interacted with ADH1B; MCM7 interacted with MCM2. BUB1B, ADH1B, and MCM2 were known CRC-related genes. Gradually upregulated expressions of CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 in stage I, II, III, and IV CRC were confirmed by using quantitative PCR. Besides, up-regulated intersection DEGs enriched in pathways about Cell cycle, DNA replication, and p53 signaling.
CONCLUSION: CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 might be CRC stage-related genes.
Grant DJ, Chen Z, Howard LE, et al.
UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression.BMC Cancer. 2017; 17(1):463 [
PubMed] Article available free on
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BACKGROUND: Uridine 5'-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.
METHODS: We determined the expression of UGT2B15, UGT2B17, and UGT2B28 enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each protein's percent positive and H-score, a weighted score of staining intensity, and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were divided at the median and we tested the association between UGT2B17 group and risk of BCR.
RESULTS: The median follow-up for all patients was 118 months (IQR: 85-144). Of 190, 83 (44%) patients developed BCR. We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend for an association between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found that patients with UGT2B17 higher levels of expression had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041), although this association was attenuated in the multivariable model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088).
CONCLUSIONS: Our findings suggest that UGT2B17 overexpression may be associated with a significant increased risk of BCR. These results are consistent with previous reports which showed UGT2B17 significantly expressed in advanced prostate cancer including prostate tumor metastases.
Zhao L, Lei H, Shen L, et al.
Prognosis genes in gastric adenocarcinoma identified by cross talk genes in disease‑related pathways.Mol Med Rep. 2017; 16(2):1232-1240 [
PubMed] Article available free on
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The aim of the present study was to investigate the prognostic value of genes that participate in the development of gastric adenocarcinoma, via exploring gene cross talk in disease‑related pathways. Differentially expressed genes (DEGs) in the gastric samples were identified by analyzing the expression data downloaded from the GEO database. The DEGs were subjected to the human protein‑protein interaction (PPI) network to construct the PPI network of DEGs, which was then used for the identification of key genes in cancer samples via the expression deviation score and degree in the network. A total of 635 DEGs, including 432 downregulated and 203 upregulated ones were screened in the gastric adenocarcinomas samples. The PPI network of DEGs comprised 590 DEGs and 4,299 interaction pairs. A total of 200 key genes were obtained, which were significantly enriched in six downregulated and six upregulated pathways. Cross talk genes in the connected pathways were analyzed, and the Kyoto Encyclopedia of Genes and Genomes pathways hsa00980 (Metabolism of xenobiotics by cytochrome P450) and hsa00982 (Drug metabolism) were reported to share 8 cross talk genes: ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B and CYP2C18. Among all cross talk genes, ADH7, ALDH3A1 and CLDN3 were the most specific genes. The high‑ and low‑risk samples identified by the prognosis model presented a remarkable difference in total survival time, indicating its robustness and sensitivity as the prognosis genes for gastric adenocarcinoma. ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B, CYP2C18ADH7, ALDH3A1 and CLDN3 may be used as the prognosis markers and target biomarkers for chemotherapies in gastric adenocarcinoma.
Chen G, Luo S, Kozlovich S, Lazarus P
Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers.Cancer Epidemiol Biomarkers Prev. 2016; 25(7):1175-1184 [
PubMed] Article available free on
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BACKGROUND: The most abundant and potent carcinogenic tobacco-specific nitrosamine in tobacco and tobacco smoke is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In vivo, NNK is rapidly metabolized to both the (R)- and (S)-enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which possesses similar carcinogenic properties as NNK. The major detoxification pathway for both NNAL enantiomers is glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes including UGT2B10 and UGT2B17. The goal of the present study was to directly examine the role of UGT genotypes on urinary levels of NNAL glucuronides in smokers.
METHODS: NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc, and free NNAL were simultaneously and directly quantified in the urine of smokers by LC/MS analysis. Genotypes were determined by TaqMan assay using genomic DNA.
RESULTS: The functional knockout polymorphism in the UGT2B10 gene at codon 67 (Asp>Tyr) was significantly (P < 0.0001) associated with a 93% decrease in creatinine-adjusted NNAL-N-Gluc. The polymorphic whole-gene deletion of the UGT2B17 gene was associated with significant (P = 0.0048) decreases in the levels of creatinine-adjusted (R)-NNAL-O-Gluc, with a 32% decrease in the levels of urinary (R)-NNAL-O-Gluc/(S)-NNAL-O-Gluc among subjects with the UGT2B17 (*2/*2) genotype as compared to subjects with the UGT2B17 (*1/*1) genotype.
CONCLUSIONS: These results suggest that functional polymorphisms in UGT2B10 and UGT2B17 are associated with a reduced detoxification capacity against NNAL and may therefore affect individual cancer risk upon exposure to tobacco.
IMPACT: This is the first report to clearly demonstrate strong genotype-phenotype associations between both the UGT2B10 codon 67 Asp
Che X, Yu D, Wu Z, et al.
Association of Genetic Polymorphisms in UDP-Glucuronosyltransferases 2B17 with the Risk of Pancreatic Cancer in Chinese Han Population.Clin Lab. 2015; 61(12):1905-10 [
PubMed]
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BACKGROUND: This study is aimed to investigate the association between polymorphisms in UGT2B17 and the risk of developing pancreatic cancer in Chinese Han population.
METHODS: A hospital-based case-control study was conducted, and 1579 healthy controls and 406 pancreatic cancer patients were enrolled. Real-time PCR was applied to identify the genetic polymorphisms in the subjects, and multivariable logistic regression analysis was performed to investigate the association between UGT2B17 polymorphisms and susceptibility to pancreatic cancer.
RESULTS: The prevalence of the UGT2B17 del/del, del/ins, and ins/ins in cases were 72.9%, 24.0%, and 3.1%, respectively, and in controls 66.6%, 30.7%, and 2.7%, respectively. Multivariable logistic regression revealed that, compared with the del/del genotype, the del/ins genotype in UGT2B17 is related to a significant reduction in pancreatic cancer risk (OR = 0.77, 95% CI = 0.60 - 0.99; P = 0.04). In the female subjects, compared with the del/del genotype, the del/ins genotype was related to a substantial reduction in pancreatic cancer risk (OR = 0.59, 95% CI = 0.39 - 0.90, P = 0.01).
CONCLUSIONS: All these results indicate a higher ratio of UGT2B17 deletion polymorphisms in Asians. UGT2B17 deletion polymorphisms are associated with the risk of developing pancreatic cancer in Chinese Han population, especially in the female population.
Zhang A, Zhang J, Plymate S, Mostaghel EA
Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression.Horm Cancer. 2016; 7(2):104-13 [
PubMed] Article available free on
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Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10, and the UGT family members UGT2B15 and UGT2B17, in controlling intratumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.
Hagberg Thulin M, Nilsson ME, Thulin P, et al.
Osteoblasts promote castration-resistant prostate cancer by altering intratumoral steroidogenesis.Mol Cell Endocrinol. 2016; 422:182-191 [
PubMed]
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The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients suggests that up-regulated steroidogenesis might contribute to tumor growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoral steroidogenesis of castration resistant prostate cancer (CRPC) in bone. We here show that osteoblasts alter the steroidogenic transcription program in CRPC cells, closely mimicking the gene expression pattern described in CRPC. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), estrogen signaling-related genes (CYP19A1, and ESR2), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15, and UGT2B17). The observed osteoblast-induced effect was exclusive to osteogenic CRPC cells (LNCaP-19) in contrast to osteolytic PC-3 and androgen-dependent LNCaP cells. The altered steroid enzymatic pattern was specific for the intratibial tumors and verified by immunohistochemistry in tissue specimens from LNCaP-19 xenograft tumors. Additionally, the overall steroidogenic effect was reflected by corresponding levels of progesterone and testosterone in serum from castrated mice with intratibial xenografts. A bi-directional interplay was demonstrated since both proliferation and Esr2 expression of osteoblasts were induced by CRPC cells in steroid-depleted conditions. Together, our results demonstrate that osteoblasts are important mediators of the intratumoral steroidogenesis of CRPC and for castration-resistant growth in bone. Targeting osteoblasts may therefore be important in the development of new therapeutic approaches.
Margaillan G, Lévesque É, Guillemette C
Epigenetic regulation of steroid inactivating UDP-glucuronosyltransferases by microRNAs in prostate cancer.J Steroid Biochem Mol Biol. 2016; 155(Pt A):85-93 [
PubMed]
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Androgens play a central role in prostate cancer progression. Systemic and local androgen bioavailability is controlled by UDP-glucuronosyltransferases conjugating enzymes (UGT), namely UGT2B15, UGT2B17 and UGT2B28. Reporter vector assays in HEK293 cells initially validated in silico-predicted regulatory potential of candidate miRNAs to target UGT transcripts, including miR-376c, miR-409 and miR-494 for UGT2B17, miR-331-5p and miR-376c for UGT2B15 while none were efficient for UGT2B28. miR-376c was shown as the most effective to downregulate UGT2B15 and UGT2B17 through interactions with a site conserved in both UGTs. Ectopic miR-376c expression in prostate cancer cells significantly reduced UGT2B15 and UGT2B17 expression (>32%; P<0.005) with a consequent decrease in dihydrotestosterone glucuronidation (-37%; P<0.001). Consistent with reduced androgen inactivation, ectopic expression of miR-376c changed expression of androgen responsive genes and enhanced cell proliferation with no effect on androgen receptor levels. Sustaining a role of miR-376c in the regulation of androgen-inactivating UGTs, its expression was significantly downregulated in prostatic tumors and further reduced in metastases (P<0.0001), whereas the opposite was observed for UGT2B15/17 (P=0.031). In high-grade tumors (Gleason ≥8), UGT2B15/17 and miR-376c were inversely correlated (r=-0.557; P=0.048) with also a significant relationship in metastases (r=-0.747; P=0.003). In line with a modification in androgen bioavailability, PSA mRNA levels were also negatively correlated to those of UGT2B15/17 (r=-0.573; P=0.01) but positively linked to levels of miR-376c (r=0.577; P=0.039). This study reveals that the androgen-inactivating UGT2B15 and UGT2B17 genes are direct targets of miR-376c and thus may influence steroid metabolism during prostate cancer progression.
Romero-Lorca A, Novillo A, Gaibar M, et al.
Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients.PLoS One. 2015; 10(7):e0132269 [
PubMed] Article available free on
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Tamoxifen is used to prevent and treat estrogen-dependent breast cancer. It is described as a prodrug since most of its antiestrogen effects are exerted through its hydroxylated metabolites 4-OH-tamoxifen and endoxifen. In prior work, we correlated optimal plasma levels of these metabolites with certain genotypes of CYP2D6 and SULT1A2. This descriptive study examines correlations between concentrations of tamoxifen's glucuronide metabolites and genotypes UGT1A4 Pro24Thr, UGT1A4 Leu48Val, UGT2B7 His268Tyr, UGT2B15 Asp85YTyr UGT2B15 Lys523Thr and UGT2B17del in 132 patients with estrogen receptor-positive breast cancer under treatment with tamoxifen. Patients were genotyped by real-time and conventional PCR-RFLP. The glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide were isolated from blood plasma and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Individuals who were homozygous for UGT1A448VAL showed significantly lower mean concentrations of both glucuronide metabolites compared to subjects genotyped as wt/wt plus wt/48Val (p=0.037 and p=0.031, respectively). Women homozygous for UGT2B7268Tyr also showed mean substrate/product ratios of 4-OH-tamoxifen/4-OH-tamoxifen-O-glucuronide and 4-OH-tamoxifen/4-OH-tamoxifen-N-glucuronide indicative of reduced glucuronidase activity compared to wt homozygotes or to heterozygotes for the polymorphism (p=0.005 and p=0.003, respectively). In contrast, UGT2B15 Lys523Thr and UGT2B17del were associated with possibly increased enzyme activity. Patients with at least one variant allele UGT2B15523Thr showed significantly higher 4-OH-tamoxifen-O-glucuronide and endoxifen-glucuronide levels (p=0.023 and p=0.025, respectively) indicating a variant gene-dose effect. Higher 4-OH-tamoxifen-N-glucuronide levels observed in UGT2B17del genotypes (p=0.042) could be attributed to a mechanism that compensates for the greater expression of other genes in UGT2B17 del/del individuals. Our observations suggest that patients carrying mutations UGT1A448Val, UGT2B7268Tyr or with wt genotypes for UGT2B17nodel and UGT2B15523Lys could be the best candidates for a good response to tamoxifen therapy in terms of eliciting effective plasma active tamoxifen metabolite levels. However, additional studies examining the effects of UGT genotype on overall patient response to TAM are needed to further examine the role of UGT polymorphisms in the therapeutic efficacy of TAM.
Wijayakumara DD, Hu DG, Meech R, et al.
Regulation of Human UGT2B15 and UGT2B17 by miR-376c in Prostate Cancer Cell Lines.J Pharmacol Exp Ther. 2015; 354(3):417-25 [
PubMed]
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Given the prime importance of UDP-glucuronosyltransferase (UGT) 2B15 and UGT2B17 in inactivating testosterone and dihydrotestosterone, control of their expression and activity in the prostate is essential for androgen signaling homeostasis in this organ. Although several studies provide evidence of transcriptional control of UGT2B15 and UGT2B17 by various endogenous and exogenous compounds, potential post-transcriptional regulation of UGT2B15 and UGT2B17 by microRNAs (miRs) in prostate cancer cells has not been examined. The present study identified a putative miR-376c target site in the 3'-untranslated regions (UTRs) of both UGT2B15 and UGT2B17 mRNAs. In accordance with the possibility that this miRNA negatively regulates UGT2B15 and UGT2B17 expression, there is an inverse correlation in the levels of miR-376c and UGT2B15/UGT2B17 mRNAs in prostate cancer cell lines versus normal prostate tissue. In LNCaP cells, transfection of miR-376c mimics inhibited the glucuronidations of testosterone, 4-methylumbelliferone (a substrate of UGT2B15), and androsterone (a substrate of UGT2B17). miR-376c reduced both UGT2B15 and UGT2B17 mRNA and protein levels and the activity of luciferase reporters containing UGT2B15 or UGT2B17 3'-UTRs. This microRNA-mediated repression was significantly abrogated by mutating the miR-376c binding site in the 3'-UTRs of both UGTs. Collectively, these data indicate that the expression of UGT2B15 and UGT2B17 is negatively regulated by the binding of miR-376c to the 3'-UTRs of UGT2B15 and UGT2B17 in prostate cancer cells. This represents the first evidence for post-transcriptional regulation of UGT2B15 and UGT2B17 by miRNAs in prostate cancer cells and may have importance in regulating androgen receptor signaling.
Mafune A, Hama T, Suda T, et al.
Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.BMC Cancer. 2015; 15:205 [
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BACKGROUND: Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse.
METHODS: We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively.
RESULTS: UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.
CONCLUSIONS: These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.
Xiang C, Wang J, Kou X, et al.
Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer.FASEB J. 2015; 29(5):1986-98 [
PubMed]
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Inhaled xenobiotics such as tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are mainly metabolized by phase I oxidase cytochrome P450, family 2, subfamily A, polypeptide 13 (CYP2A13), phase II conjugate UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17), and phase III transporter ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1), with genetic polymorphisms implicated in lung cancer. Their genetic interaction and pulmonary expression regulation are largely unknown. We analyzed joint association for CYP2A13 and ABCB1 polymorphisms in 2 independent lung cancer case populations (669 and 566 patients) and 1 common control population (749 subjects), and characterized the trans-acting function of the lung development-related transcription factor forkhead box A2 (FOXA2). We undertook FOXA2 overexpression and down-regulation in lung epithelial cell lines, analyzed functional impact on the transactivation of CYP2A13, UGT2B17, and ABCB1, and measured correlation for their expressions in lung tissues. We found a substantial reduction in cancer risk (OR 0.39; 95% CI 0.25-0.61; Pinteraction = 0.029) associated with combined genotypes for CYP2A13 R257C and a functionary regulatory variant in the cis element of ABCB1 synergistically targeted by GATA binding protein 6 and FOXA2. Genetic manipulation of FOXA2 consistently influenced its binding to and transactivation of the promoters of CYP2A13, UGT2B17, and ABCB1, whose mRNA and protein expressions were all consistently correlated with those of FOXA2 in both tumorous and normal lung tissues. We therefore establish FOXA2 as a core transcriptional modulator for pulmonary xenobiotic metabolic pathways and uncover an etiologically relevant interaction between CYP2A13 and ABCB1, furthering our understanding of expression and function of the xenobiotic metabolism system.
Gauthier-Landry L, Bélanger A, Barbier O
Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution.J Steroid Biochem Mol Biol. 2015; 145:187-92 [
PubMed]
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In the prostate, approximately 50% of androgens are from adrenal steroids, mainly dehydroepiandrosterone (DHEA), its sulfate and androstenedione. These compounds are converted first into testosterone, and then into the active hormone dihydrotestosterone (DHT). After having activated the androgen receptor (AR), DHT is reduced into androstane-3α-DIOL (3α-DIOL) and androsterone (ADT), which are subsequently converted into 2 inactive and easily excretable metabolites: 3α-DIOL-17glucuronide (3α-DIOL-17G) and ADT-3glucuronide (ADT-3G). The formation of these last derivatives through the glucuronidation reaction involves 2 UDP-glucuronosyltransferase (UGT) enzymes, namely UGT2B15 and UGT2B17. The present review article aims at providing a comprehensive view of the physiological and pharmacological importance of these 2 enzymes for the control of androgen homeostasis. We will resume: (i) how UGT2B15 and UGT2B17 contribute to androgen elimination; (ii) how their glucuronidation capacity influences the androgen signaling pathway in prostate cells; (iii) how they contribute to the anti-proliferative properties of AR antagonists in prostate cancer cells; and (iv) how AR and its spliced variants regulate the UGT2B15 and/or UGT2B17 genes expression. Finally, whether the unexploited AR-UGT axis could serve as a prognostic maker or a pharmacological target for novel therapeutics in the treatment of prostate cancer is also discussed. This article is part of a special issue entitled 'Essential role of DHEA'.
Vidal AC, Tucker C, Schildkraut JM, et al.
Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study.BMC Cancer. 2013; 13:556 [
PubMed] Article available free on
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BACKGROUND: We have previously shown that a functional polymorphism of the UGT2B15 gene (rs1902023) was associated with increased risk of prostate cancer (PC). Novel functional polymorphisms of the UGT2B17 and UGT2B15 genes have been recently characterized by in vitro assays but have not been evaluated in epidemiologic studies.
METHODS: Fifteen functional SNPs of the UGT2B17 and UGT2B15 genes, including cis-acting UGT2B gene SNPs, were genotyped in African American and Caucasian men (233 PC cases and 342 controls). Regression models were used to analyze the association between SNPs and PC risk.
RESULTS: After adjusting for race, age and BMI, we found that six UGT2B15 SNPs (rs4148269, rs3100, rs9994887, rs13112099, rs7686914 and rs7696472) were associated with an increased risk of PC in log-additive models (p < 0.05). A SNP cis-acting on UGT2B17 and UGT2B15 expression (rs17147338) was also associated with increased risk of prostate cancer (OR = 1.65, 95% CI = 1.00-2.70); while a stronger association among men with high Gleason sum was observed for SNPs rs4148269 and rs3100.
CONCLUSIONS: Although small sample size limits inference, we report novel associations between UGT2B15 and UGT2B17 variants and PC risk. These associations with PC risk in men with high Gleason sum, more frequently found in African American men, support the relevance of genetic differences in the androgen metabolism pathway, which could explain, in part, the high incidence of PC among African American men. Larger studies are required.
Grosse L, Pâquet S, Caron P, et al.
Androgen glucuronidation: an unexpected target for androgen deprivation therapy, with prognosis and diagnostic implications.Cancer Res. 2013; 73(23):6963-71 [
PubMed]
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Androgen deprivation therapy (ADTh) remains a mainstay of prostate cancer treatment, but its efficacy is bypassed by mechanisms that are not fully understood. In human prostate cancer cells, androgen glucuronidation, catalyzed by the two UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17, is the major androgen inactivation pathway. In this study, we investigated the effect of ADTh on androgen glucuronidation to evaluate its potential clinical utility for prostate cancer prognosis or therapy. UGT2B15 and UGT2B17 expression was evaluated in prostate cancer specimens from untreated or treated patients and in cell models of prostate cancer exposed to clinically relevant antiandrogens. UGT2B15 and UGT2B17 protein levels in prostate were increased after 5 months of ADTh when compared with specimens from untreated patients. UGT2B15 expression remained elevated for up to 12 months, but UGT2B17 returned to initial levels as soon as after 6 months. Several androgen receptor (AR) antagonists tested caused a dose- and time-dependent stimulation of UGT2B15 and UGT2B17 expression and androgen glucuronidation in prostate cancer cell lines. The role of AR in these regulatory events was confirmed using AR-deficient LNCaP cells, in which UGT2B attenuation reduced the antiproliferative effects of AR pharmacologic antagonists. Through this combination of clinical and functional investigations, our work revealed that ADTh stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of UGT2B15 and UGT2B17 as drug targets and/or molecular markers for ADTh responsiveness and maintenance in prostate cancer.
Gruber M, Le T, Filipits M, et al.
UDP-glucuronosyltransferase 2B17 genotype and the risk of lung cancer among Austrian Caucasians.Cancer Epidemiol. 2013; 37(5):625-8 [
PubMed]
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BACKGROUND: The enzyme uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) glucuronidates several endogenous and exogenous compounds, including carcinogens from tobacco smoke like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanl (NNAL). UGT2B17 shows a remarkable copy number variation (CNV) and an association between deletion genotype and increased risk of lung adenocarcinoma in women has been previously reported.
METHODS: We investigated the UGT2B17 CNV by PCR in 453 Austrian lung cancer patients and in 449 healthy donors and analyzed the impact on lung cancer susceptibility and outcome.
RESULTS: Copy numbers of UGT2B17 were 44.4% (+/+), 42.2% (+/-) and 13.5% (-/-) in lung cancer patients and 43.0% (+/+), 46.3% (+/-) and 10.7% (-/-) among healthy donors. The null genotype was not significantly more frequent among women with adenocarcinoma compared to healthy women (p=0.59). There was no association with overall survival (p=0.622) and no significant sex-associated (p=0.423) or histology-related impact on development of lung cancer.
CONCLUSION: UGT2B17 deletion genotype was not associated with a significant risk for lung cancer development or outcome in our Central European patient cohort. Our study indicates that UGT2B17 is not a crucial factor in lung carcinogenesis among Caucasians and shows the importance of investigating such markers in large cohorts from different populations.
Malhotra A, Shibata Y, Hall IM, Dutta A
Chromosomal structural variations during progression of a prostate epithelial cell line to a malignant metastatic state inactivate the NF2, NIPSNAP1, UGT2B17, and LPIN2 genes.Cancer Biol Ther. 2013; 14(9):840-52 [
PubMed] Article available free on
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Prostate cancer is the second highest cause of male cancer deaths in the United States. A significant number of tumors advance to a highly invasive and metastatic stage, which is typically resistant to traditional cancer therapeutics. In order to identify chromosomal structural variants that may contribute to prostate cancer progression we sequenced the genomes of a HPV-18 immortalized nonmalignant human prostate epithelial cell line, RWPE1, and compared it to its malignant, metastatic derivative, WPE1-NB26. There were a total of 34 large (> 1 Mbp) and 38 small copy number variants (<100 kbp) in WPE1-NB26 that were not present in the precursor cell line. We also identified and validated 46 structural variants present in the two cell lines, of which 23 were unique to WPE1-NB26. Structural variants unique to the malignant cell line inactivated: (1) the neurofibromin2 (NF2) gene, a known tumor suppressor; (2) its neighboring gene NIPSNAP1, another putative tumor suppressor that inhibits TRPV6, an anti-apoptotic oncogene implicated in prostate cancer progression; (3) UGT2B17, a gene that inactivates dihydrotestosterone, a known activator of prostate cancer progression; and (4) LPIN2, a phosphatidic acid phosphatase and a co-factor of PGC1a that is important for lipid metabolism and for suppressing autoinflammation. Our results illustrate the value of comparing the genomes of defined related pairs of cell lines to discover chromosomal structural variants that may contribute to cancer progression.
Angstadt AY, Berg A, Zhu J, et al.
The effect of copy number variation in the phase II detoxification genes UGT2B17 and UGT2B28 on colorectal cancer risk.Cancer. 2013; 119(13):2477-85 [
PubMed] Article available free on
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BACKGROUND: Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome.
METHODS: To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires.
RESULTS: A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P = .044). Stratification by sex yielded a decreased risk (P = .020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P = .724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P = .0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk.
CONCLUSIONS: The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.
Nakka M, Agoulnik IU, Weigel NL
Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells.Int J Biochem Cell Biol. 2013; 45(4):763-72 [
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The evidence that androgen blockade-resistant prostate cancer, termed castration resistant, remains androgen receptor (AR) dependent is compelling. AR is re-activated through multiple mechanisms including expression of constitutively active splice variants that lack hormone binding domains (HBDs). This highlights the need to develop therapies that target regions other than the HBD. Because the p160 coactivators interact most strongly with the amino-terminus of AR, we examined the consequences of disrupting this interaction. We identified two overlapping SRC-1 peptides that interact with AR, but not with progesterone receptor. These peptides reduce AR and AR variant AR-V7 dependent induction of an AR responsive reporter. Using mammalian two hybrid assays, we found that the peptides interrupt the AR/SRC-1, AR/SRC-2 and AR N/C interactions, but not SRC-1/CARM-1 interactions. Consistent with the SRC-1 dependence of induced, but not repressed genes, in LNCaP cells, the peptides inhibited hormone dependent induction of endogenous target genes including PSA and TMPRSS2, but did not block AR dependent repression of UGT2B17 or inhibit vitamin D receptor activity. Simultaneous detection of SRC-1 peptides and PSA by double immunofluorescence in transfected LNCaP cells clearly demonstrated a strong reduction in PSA levels in cells expressing the peptides. The peptides also inhibited the AR dependent expression of PSA in castration resistant C4-2 cells. Moreover they inhibited androgen dependent proliferation of LNCaP cells and proliferation of C4-2 cells in androgen depleted medium without affecting AR negative PC-3 cells. Thus, the p160 coactivator binding site is a novel potential therapeutic target to inhibit AR activity.
Gruber M, Bellemare J, Hoermann G, et al.
Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high-risk chronic lymphocytic leukemia.Blood. 2013; 121(7):1175-83 [
PubMed]
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Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) glucuronidates androgens and xenobiotics including certain drugs. The UGT2B17 gene shows a remarkable copy number variation (CNV), which predisposes for solid tumors and influences drug response. Here, we identify a yet undescribed UGT2B17 mRNA overexpression in poor-risk chronic lymphocytic leukemia (CLL). In total, 320 CLL patients and 449 healthy donors were analyzed. High (above median) UGT2B17 expression was associated with established CLL poor prognostic factors and resulted in shorter treatment-free and overall survival (hazard ratio ([death] 2.18; 95% CI 1.18-4.01; P = .013). The prognostic impact of mRNA expression was more significant than that of UGT2B17 CNV. UGT2B17 mRNA levels in primary CLL samples directly correlated with functional glucuronidation activity toward androgens and the anticancer drug vorinostat (R > 0.9, P < .001). After treatment with fludarabine containing regimens UGT2B17 was up-regulated particularly in poor responders (P = .030). We observed an exclusive involvement of the 2B17 isoform within the UGT protein family. Gene expression profiling of a stable UGT2B17 knockdown in the CLL cell line MEC-1 demonstrated a significant involvement in key cellular processes. These findings establish a relevant role of UGT2B17 in CLL with functional consequences and potential therapeutic implications.
Grant DJ, Hoyo C, Oliver SD, et al.
Association of uridine diphosphate-glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk.Genet Test Mol Biomarkers. 2013; 17(1):3-9 [
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AIMS: Uridine diphosphate-glucuronosyltransferase 2B (UGT2B) enzymes conjugate testosterone metabolites to enable their excretion in humans. The functional significance of the UGT2B genetic variants has never been described in humans. We evaluated UGT2B variants in relation to plasma androstane-3α,17β-diol-glucuronide (AAG) levels and the prostate cancer risk.
RESULTS: AAG levels were measured in sera from 150 controls and compared to the polymorphisms of UGT2B17, UGT2B15, and UGT2B7. Genomic DNA from controls (301) and cases (148) was genotyped for the polymorphisms, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analyses. Having two copies of UGT2B17 was associated with higher AAG levels in controls among Whites (p=0.02), but not Blacks (p=0.82). Logistic regression models adjusting for age and race revealed that homozygosity for the G allele of the UGT2B15(D85Y) polymorphism was directly associated with the prostate cancer risk (OR=2.70, 95% CI=1.28, 5.55).
CONCLUSIONS: While the small sample size limits inference, our findings suggest that an association between the UGT2B17 copy number variant (CNV) and serum AAG levels in Whites, but unexpectedly not in Blacks. This novel observation suggests that genetic determinants of AAG levels in Blacks are unrelated to the UGT2B17 CNV. This study replicates the results that show an association of UGT215(D85Y) with an increased prostate cancer risk.