RXRA | Cancer Genetics Web

MTOR

Xia Y, Cheng X, Li Y, et al.
Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype.
J Virol. 2018; 92(19) [PubMed] Free Access to Full Article Related Publications

Hepatitis B virus (HBV) infection is a major health problem worldwide, and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. Using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and signaling pathways of infected hepatocytes and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of the transforming growth factor β (TGF-β) family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 genes associated with the cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G

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Liver Cancer

O'Brien KM, Sandler DP, Xu Z, et al.
Vitamin D, DNA methylation, and breast cancer.
Breast Cancer Res. 2018; 20(1):70 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation.
METHODS: We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort.
RESULTS: Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 × 10
CONCLUSIONS: 25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer.

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CYP24A1

Halstead AM, Kapadia CD, Bolzenius J, et al.
Bladder-cancer-associated mutations in
Elife. 2017; 6 [PubMed] Free Access to Full Article Related Publications

RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of

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Goldstein JT, Berger AC, Shih J, et al.
Genomic Activation of
Cancer Res. 2017; 77(24):6987-6998 [PubMed] Free Access to Full Article Related Publications

The

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PPARG

O'Brien KM, Sandler DP, Kinyamu HK, et al.
Single-Nucleotide Polymorphisms in Vitamin D-Related Genes May Modify Vitamin D-Breast Cancer Associations.
Cancer Epidemiol Biomarkers Prev. 2017; 26(12):1761-1771 [PubMed] Free Access to Full Article Related Publications

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Colorectal (Bowel) Cancer

Zhi X, Tao J, Zhang L, et al.
Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating Hedgehog signaling pathway in colorectal cancer.
Cell Death Dis. 2016; 7(12):e2569 [PubMed] Free Access to Full Article Related Publications

Epigenetic silencing of tumor suppressors contributes to the development and progression of colorectal cancer (CRC). We recently found that speckle-type POZ protein (SPOP) was significantly downregulated and the inactivation of SPOP promoted metastasis in CRC. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in CRC. Our results revealed that the core region of SPOP promoter was hypermethylated in CRC tissues and its methylation was correlated with poor survival. Transcription factor RXRA had a vital role in the regulation of SPOP gene. The data indicated that DNA methylation at -167 bp of the SPOP gene altered the binding affinity between transcription factor RXRA and SPOP promoter. Moreover, SPOP was found to associate with Gli2 and promoted its ubiquitination and degradation in CRC. Consequently, the expression level of Hh/Gli2 pathway-related apoptotic protein Bcl-2 was decreased and the function of resisting cell death was inhibited in CRC. It suggests that methylation status of SPOP promoter can be used as a novel epigenetic biomarker and a therapeutic target in CRC.

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Apoptosis

Churchman ML, Mullighan CG
Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia.
Exp Hematol. 2017; 46:1-8 [PubMed] Free Access to Full Article Related Publications

Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high-risk B-progenitor acute lymphoblastic leukemia (ALL), such as BCR-ABL1-positive (Ph+) and Ph-like ALL, and are associated with poor outcome even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiation, skewing lineage of leukemia from myeloid to lymphoid, and, in Ph+ leukemia, conferring resistance to tyrosine kinase inhibitor (TKI) therapy without abrogating ABL1 inhibition. These effects are in part mediated by acquisition of an aberrant hematopoietic stem cell-like program accompanied by induction of cell surface expression of stem cell and adhesion molecules that mediate extravascular invasion and residence in the niche and activation of integrin signaling pathways. These effects can be exploited therapeutically using several approaches. IKZF1 alterations also result in upregulation of RXRA that encodes part of the heterodimeric retinoic acid X receptor. Rexinoids, a synthetic class of retinoids that bind specifically to retinoid "X" receptors such as bexarotene potently reverse aberrant adhesion and niche mislocalization in vivo and induce differentiation and cell cycle arrest. Focal adhesion kinase inhibitors block the downstream integrin-mediated signaling, reverse adhesion, and niche mislocalization. Both agents act synergistically with TKIs to prolong survival of Ph+ ALL in mouse and human xenograft model, with long-term remission induced by focal adhesion kinase inhibitors. Therefore, these findings provide important new conceptual insights into the mechanisms by which IKZF1 alterations result in drug resistance and indicate that therapeutic strategies directed against the pathways deregulated by mutation, rather than attempting to restore IKZF1 expression directly, represent promising therapeutic approaches in this disease.

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Laé M, Gardrat S, Rondeau S, et al.
MED12 mutations in breast phyllodes tumors: evidence of temporal tumoral heterogeneity and identification of associated critical signaling pathways.
Oncotarget. 2016; 7(51):84428-84438 [PubMed] Free Access to Full Article Related Publications

Exome sequencing has recently identified highly recurrent MED12 somatic mutations in fibroadenomas (FAs) and phyllodes tumors (PTs). In the present study, based on a large series, we confirmed the presence of MED12 exon 1 and 2 mutations in 49% (41/83) of PTs, 70% (7/10) of FAs and 9.1% (1/11) of fibromatoses. We show that MED12 mutations are associated with benign behavior of phyllodes tumors, as they are detected less frequently in malignant PTs (27.6%) compared to benign (58.3%) and borderline (63.3%) PTs, respectively (p = 0.0036). Phyllodes tumors presented marked temporal heterogeneity of MED12 mutation status, as 50% (3/6) of primary and recurrent phyllodes tumor pairs with MED12 mutation presented different MED12 mutations between the primary and recurrent tumors. There was no correlation between MED12 status and genomic profiles obtained by array-CGH. MED12 mutations are associated with altered expressions of the genes involved in the WNT (PAX3, WNT3A, AXIN2), TGFB (TAGLN, TGFBR2, CTGF) and THRA (RXRA, THRA) signaling pathways.In conclusion, this study confirmed that MED12 plays a central oncogenic role in breast fibroepithelial tumorigenesis and identified a limited number of altered signaling pathways that maybe associated with MED12 mutations. MED12 exon 1 and 2 mutation status and some of the altered genes identified in this study could constitute useful diagnostic or prognostic markers, and form the basis for novel therapeutic strategies for PTs.

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Ward DG, Baxter L, Gordon NS, et al.
Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.
PLoS One. 2016; 11(2):e0149756 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA.
METHODS: DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free).
RESULTS: Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity).
CONCLUSION: This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.

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Yin J, Liu H, Yi X, et al.
Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival.
Pigment Cell Melanoma Res. 2016; 29(2):176-85 [PubMed] Free Access to Full Article Related Publications

Single nucleotide polymorphisms (SNPs) in the vitamin D pathway genes have been implicated in cutaneous melanoma (CM) risk, but their role in CM disease-specific survival (DSS) remains obscure. We comprehensively analyzed the prognostic roles of 2669 common SNPs in the vitamin D pathway genes using data from a published genome-wide association study (GWAS) at The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated the SNPs of interest in another GWAS from the Nurses' Health Study and Health Professionals Follow-up Study. Among the 2669 SNPs, 203 were significantly associated with DSS in MDACC dataset (P < 0.05 and false-positive report probability < 0.2), of which 18 were the tag SNPs. In the replication, two of these 18 SNPs showed nominal significance: the VDBP rs12512631 T > C was associated with a better DSS [combined hazards ratio (HR) = 0.66]; and the same for RXRA rs7850212 C > A (combined HR = 0.38), which were further confirmed by the Fine and Gray competing-risks regression model. Further bioinformatics analyses indicated that these loci may modulate corresponding gene methylation status.

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Melanoma

Skin Cancer

Day FR, Bulik-Sullivan B, Hinds DA, et al.
Shared genetic aetiology of puberty timing between sexes and with health-related outcomes.
Nat Commun. 2015; 6:8842 [PubMed] Free Access to Full Article Related Publications

Understanding of the genetic regulation of puberty timing has come largely from studies of rare disorders and population-based studies in women. Here, we report the largest genomic analysis for puberty timing in 55,871 men, based on recalled age at voice breaking. Analysis across all genomic variants reveals strong genetic correlation (0.74, P=2.7 × 10(-70)) between male and female puberty timing. However, some loci show sex-divergent effects, including directionally opposite effects between sexes at the SIM1/MCHR2 locus (Pheterogeneity=1.6 × 10(-12)). We find five novel loci for puberty timing (P<5 × 10(-8)), in addition to nine signals in men that were previously reported in women. Newly implicated genes include two retinoic acid-related receptors, RORB and RXRA, and two genes reportedly disrupted in rare disorders of puberty, LEPR and KAL1. Finally, we identify genetic correlations that indicate shared aetiologies in both sexes between puberty timing and body mass index, fasting insulin levels, lipid levels, type 2 diabetes and cardiovascular disease.

Clendenen TV, Ge W, Koenig KL, et al.
Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study.
PLoS One. 2015; 10(10):e0140478 [PubMed] Free Access to Full Article Related Publications

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

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CYP24A1

Malouf GG, Tahara T, Paradis V, et al.
Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features.
Epigenetics. 2015; 10(9):872-81 [PubMed] Free Access to Full Article Related Publications

With the goal of studying epigenetic alterations in fibrolamellar hepatocellular carcinoma (FLC) and establish an associated DNA methylation signature, we analyzed LINE-1 methylation in a cohort of FLC and performed next-generation sequencing of DNA methylation in a training set of pure-FLCs and non-cirrhotic hepatocellular carcinomas (nc-HCC). DNA methylation was correlated with gene expression. Furthermore, we established and validated an epigenetic signature differentiating pure-FLC from other HCCs. LINE-1 methylation correlated with shorter recurrence-free survival and overall survival in resected pure-FLC patients. Unsupervised clustering using CG sites located in islands distinguished pure-FLC from nc-HCC. Major DNA methylation changes occurred outside promoters, mainly in gene bodies and intergenic regions located in the vicinity of liver developmental genes (i.e., SMARCA4 and RXRA). Partially methylated domains were more prone to DNA methylation changes. Furthermore, we identified several putative tumor suppressor genes (e.g., DLEU7) and oncogenes (e.g., DUSP4). While ∼ 70% of identified gene promoters gaining methylation were marked by bivalent histone marks (H3K4me3/H3K27me3) in embryonic stem cells, ∼ 70% of those losing methylation were marked by H3K4me3. Finally, we established a pure FLC DNA methylation signature and validated it in an independent dataset. Our analysis reveals a distinct epigenetic signature of pure FLC as compared to nc-HCC, with DNA methylation changes occurring in the vicinity of liver developmental genes. These data suggest new options for targeting FLC based on cancer epigenome aberrations.

Eriksson P, Aine M, Veerla S, et al.
Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems.
BMC Med Genomics. 2015; 8:25 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized.
METHODS: In this study, we use publically available ChIP-Seq data on regulatory factor binding in order to link transcription factors to gene signatures defining molecular subtypes of urothelial carcinoma.
RESULTS: We identify PPARG and STAT3, as well as ADIRF, a novel regulator of fatty acid metabolism, as putative mediators of the SCC-like phenotype. We link the PLK1-FOXM1 axis to the rapidly proliferating Genomically Unstable and SCC-like subtypes and show that differentiation programs involving PPARG/RXRA, FOXA1/GATA3 and HOXA/HOXB are differentially expressed in UC molecular subtypes. We show that gene signatures and regulatory systems defined in urothelial carcinoma operate in breast cancer in a subtype specific manner, suggesting similarities at the gene regulatory level of these two tumor types.
CONCLUSIONS: At the gene regulatory level Urobasal, Genomically Unstable and SCC-like tumors represents three fundamentally different tumor types. Urobasal tumors maintain an apparent urothelial differentiation axis composed of PPARG/RXRA, FOXA1/GATA3 and anterior HOXA and HOXB genes. Genomically Unstable and SCC-like tumors differ from Urobasal tumors by a strong increase of proliferative activity through the PLK1-FOXM1 axis operating in both subtypes. However, whereas SCC-like tumors evade urothelial differentiation by a block in differentiation through strong downregulation of PPARG/RXRA, FOXA1/GATA3, our data indicates that Genomically Unstable tumors evade differentiation in a more dynamic manner.

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Sangeetha M, Deepa PR, Rishi P, et al.
Global gene deregulations in FASN silenced retinoblastoma cancer cells: molecular and clinico-pathological correlations.
J Cell Biochem. 2015; 116(11):2676-94 [PubMed] Related Publications

Activation of fatty acid synthase (FASN) enzyme in the de novo lipogenic pathway has been reported in various cancers including retinoblastoma (RB), a pediatric ocular cancer. The present study investigates lipogenesis-dependent survival of RB cancer cells and the associated molecular pathways in FASN silenced RB cells. The siRNA-mediated FASN gene knockdown in RB cancer cells (Y79, WERI RB1) repressed FASN mRNA and protein expressions, and decreased cancer cell viability. Global gene expression microarray analysis was performed in optimized FASN siRNA transfected and untransfected RB cells. Deregulation of various downstream cell signaling pathways such as EGFR (n = 55 genes), TGF-beta (n = 45 genes), cell cycle (n = 41 genes), MAPK (n = 39 genes), lipid metabolism (n = 23 genes), apoptosis (n = 21 genes), GPCR signaling (n = 21 genes), and oxidative phosporylation (n = 18 genes) were observed. The qRT-PCR validation in FASN knockdown RB cells revealed up-regulation of ANXA1, DAPK2, and down-regulation of SKP2, SREBP1c, RXRA, ACACB, FASN, HMGCR, USP2a genes that favored the anti-cancer effect of lipogenic inhibition in RB. The expression of these genes in primary RB tumor tissues were correlated with FASN expression, based on their clinico-pathological features. The differential phosphorylation status of the various PI3K/AKT pathway proteins (by western analysis) indicated that the FASN gene silencing indeed mediated apoptosis in RB cells through the PI3K/AKT pathway. Scratch assay clearly revealed that FASN silencing reduced the invading property of RB cancer cells. Dependence of RB cancer cells on lipid metabolism for survival and progression is implicated. Thus targeting FASN is a promising strategy in RB therapy.

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Retinoblastoma

Tombolan L, Zampini M, Casara S, et al.
MicroRNA-27a Contributes to Rhabdomyosarcoma Cell Proliferation by Suppressing RARA and RXRA.
PLoS One. 2015; 10(4):e0125171 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Rhabdomyosarcomas (RMS) are rare but very aggressive childhood tumors that arise as a consequence of a regulatory disruption in the growth and differentiation pathways of myogenic precursor cells. According to morphological criteria, there are two major RMS subtypes: embryonal RMS (ERMS) and alveolar RMS (ARMS) with the latter showing greater aggressiveness and metastatic potential with respect to the former. Efforts to unravel the complex molecular mechanisms underlying RMS pathogenesis and progression have revealed that microRNAs (miRNAs) play a key role in tumorigenesis.
METHODOLOGY/PRINCIPAL FINDINGS: The expression profiles of 8 different RMS cell lines were analyzed to investigate the involvement of miRNAs in RMS. The miRNA population from each cell line was compared to a reference sample consisting of a balanced pool of total RNA extracted from those 8 cell lines. Sixteen miRNAs whose expression discriminates between translocation-positive ARMS and negative RMS were identified. Attention was focused on the role of miR-27a that is up-regulated in the more aggressive RMS cell lines (translocation-positive ARMS) in which it probably acts as an oncogene. MiR-27a overexpressing cells showed a significant increase in their proliferation rate that was paralleled by a decrease in the number of cells in the G1 phase of the cell cycle. It was possible to demonstrate that miR-27a is implicated in cell cycle control by targeting the retinoic acid alpha receptor (RARA) and retinoic X receptor alpha (RXRA).
CONCLUSIONS: Study results have demonstrated that miRNA expression signature profiling can be used to classify different RMS subtypes and suggest that miR-27a may have a therapeutic potential in RMS by modulating the expression of retinoic acid receptors.

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MicroRNAs

RARA

Rhabdomyosarcoma

Giardina C, Nakanishi M, Khan A, et al.
Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas.
Cancer Prev Res (Phila). 2015; 8(5):387-99 [PubMed] Free Access to Full Article Related Publications

One variable that may affect the ability of vitamin D to reduce colon cancer risk is the expression of its high-affinity receptor, VDR. Here, we show that vitamin D does not reduce tumor formation in Apc(Δ14/+) mice and that VDR expression is lost in the majority of the colon tumor cells. The extent of VDR loss corresponded inversely to the level of β-catenin nuclear localization and could be observed in early lesions composed of just a few crypts. Analysis of reported VDR regulators showed that the repressing class I histone deacetylases (HDAC) were significantly elevated in the tumors (up to 4-fold), whereas the VDR-activating retinoid X receptors (RXR) were downregulated (∼50%). Expression of the Slug repressor was also increased, but was found primarily in stromal cells. Analysis of epigenetically active compounds on colon cell lines and intestinal organoids showed that HDAC inhibitors were particularly adept at stimulating VDR expression. Treatment of tumor-bearing Apc(Δ14/+) mice with the HDAC inhibitor panobinostat increased VDR expression in the tumors and normal mucosa. The RXR agonist bexarotene failed to activate VDR expression, indicating that RXR ligands were not limiting. Analysis of human microarray data indicated that VDR mRNA is frequently downregulated in colon adenomas, which correlated positively with RXRA expression and inversely with HDAC 2 and 8 expression. Human adenomas showed variable VDR protein expression levels, both between and within individual lesions. Determining the mechanisms of VDR regulation in colon neoplasms may significantly enhance our ability to use vitamin D as a cancer prevention agent.

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APC

Arem H, Yu K, Xiong X, et al.
Vitamin D metabolic pathway genes and pancreatic cancer risk.
PLoS One. 2015; 10(3):e0117574 [PubMed] Free Access to Full Article Related Publications

Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.

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Cancer of the Pancreas

Pancreatic Cancer

Qiu JJ, Zeisig BB, Li S, et al.
Critical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia.
Leukemia. 2015; 29(5):1153-62 [PubMed] Related Publications

While the nucleoporin 98-retinoic acid receptor gamma (NUP98-RARG) is the first RARG fusion protein found in acute leukemia, its roles and the molecular basis in oncogenic transformation are currently unknown. Here, we showed that homodimeric NUP98-RARG not only acquired unique nuclear localization pattern and ability of recruiting both RXRA and wild-type NUP98, but also exhibited similar transcriptional properties as RARA fusions found in acute promyelocytic leukemia (APL). Using murine bone marrow retroviral transduction/transformation assay, we further demonstrated that NUP98-RARG fusion protein had gained transformation ability of primary hematopoietic stem/progenitor cells, which was critically dependent on the C-terminal GLFG domain of NUP98 and the DNA binding domain (DBD) of RARG. In contrast to other NUP98 fusions, cells transformed by the NUP98-RARG fusion were extremely sensitive to all-trans retinoic acid (ATRA) treatment. Interestingly, while pan-RXR agonists, SR11237 and LGD1069 could specifically inhibit NUP98-RARG transformed cells, mutation of the RXR interaction domain in NUP98-RARG had little effect on its transformation, revealing that therapeutic functions of rexinoid can be independent of the direct biochemical interaction between RXR and the fusion. Together, these results indicate that deregulation of the retinoid/rexinoid signaling pathway has a major role and may represent a potential therapeutic target for NUP98-RARG-mediated transformation.

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Leukemia

NUP98

Vitaliano-Prunier A, Halftermeyer J, Ablain J, et al.
Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation.
Blood. 2014; 124(25):3772-80 [PubMed] Related Publications

PML/RARA, a potent transcriptional inhibitor of nuclear receptor signaling, represses myeloid differentiation genes and drives acute promyelocytic leukemia (APL). Association of the retinoid X receptor-α (RXRA) coreceptor to PML/RARA is required for transformation, with RXRA promoting its efficient DNA binding. APL is exquisitely sensitive to retinoic acid (RA) and arsenic trioxide (arsenic), which both trigger cell differentiation in vivo. Whereas RA elicits transcriptional activation of PML/RARA targets, how arsenic triggers differentiation remains unclear. Here we demonstrate that extinction of PML/RARA triggers terminal differentiation in vivo. Similarly, ablation of retinoid X receptors loosens PML/RARA DNA binding, inducing terminal differentiation of APL cells ex vivo or in vivo. RXRA sumoylation directly contributes to PML/RARA-dependent transformation ex vivo, presumably by enhancing transcriptional repression. Thus, APL differentiation is a default program triggered by clearance of PML/RARA-bound promoters, rather than obligatory active transcriptional activation, explaining how arsenic elicits APL maturation through PML/RARA degradation.

Welch JS, Niu H, Uy GL, et al.
A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML.
Am J Hematol. 2014; 89(8):E103-8 [PubMed] Free Access to Full Article Related Publications

The response rate of non-M3 acute myeloid leukemia (AML) to all trans retinoic acid has been limited. Using Affymetrix expression arrays, we found that in diverse AML blasts RXRA was expressed at higher levels than RARA and that mouse Ctsg-PML-RARA leukemia responded to bexarotene, a ligand for RXRA. We therefore performed a phase I study of combination bexarotene and decitabine in elderly and relapsed AML patients. We found that this combination was well tolerated, although outcomes were modest (1 CRi, and 3 PR among 19 patients). Correlative studies found that patients with clinical response had increased differentiation to bexarotene both in vivo and ex vivo, suggesting that pre-treatment analysis might identify a more susceptible subgroup of patients.

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Azacitidine

RARA

De Braekeleer E, Douet-Guilbert N, De Braekeleer M
RARA fusion genes in acute promyelocytic leukemia: a review.
Expert Rev Hematol. 2014; 7(3):347-57 [PubMed] Related Publications

The t(15;17)(q24;q21), generating a PML-RARA fusion gene, is the hallmark of acute promyelocytic leukemia (APL). At present, eight other genes fusing with RARA have been identified. The resulting fusion proteins retain domains of the RARA protein allowing binding to retinoic acid response elements (RARE) and dimerization with the retinoid X receptor protein (RXRA). They participate in protein-protein interactions, associating with RXRA to form hetero-oligomeric complexes that can bind to RARE. They have a dominant-negative effect on wild-type RARA/RXRA transcriptional activity. Moreover, RARA fusion proteins can homodimerize, conferring the ability to regulate an expanded repertoire of genes normally not affected by RARA. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of ATRA or arsenic trioxide. However, resistance to these two drugs is a major problem, which necessitates development of new therapies.

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RARA

Chew SC, Lim J, Singh O, et al.
Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) on docetaxel disposition in Chinese nasopharyngeal cancer patients.
Eur J Clin Pharmacol. 2014; 70(2):155-66 [PubMed] Related Publications

PURPOSE: This exploratory study was aimed at elucidating the pharmacogenetics of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) and their implications on docetaxel pharmacokinetics and pharmacodynamics in local Chinese nasopharyngeal cancer patients.
METHODS: A total of 59 single nucleotide polymorphisms (SNPs), including tag-SNPs and functionally relevant SNPs of the genes encoding these regulatory nuclear receptors (PXR/NR1I2, CAR/NR1I3, RXRα/NR2B1 and HNF4α/NR2A1), were profiled in the patients enrolled in our study by direct sequencing (N = 50). The generalized linear model was employed to estimate the haplotypic effects on the pharmacokinetics and pharmacodynamics of the patients.
RESULTS: The pharmacokinetic profiles of docetaxel in these patients were characterized by marked interindividual variability, with approximately four- to sixfold variations observed in Cmax, AUC0-∞ and CL. Individual SNP association tests revealed that polymorphisms in NR2B1 and NR2A1 were significantly correlated with altered docetaxel pharmacokinetics. Subsequent haplotype association analysis identified the NR2B1 LD block 2 AG haplotype [*+4458G>A(rs3132291) and *+4988A>G(rs4842198)] to be significantly associated with altered pharmacokinetics, in which patients carrying two copies of the AG haplotype had approximately a 20 % decreased Cmax and AUC0-∞ and a 21 % increased CL compared to those who carried only one copy or no copies of the haplotype. A number of SNPs in NR1I2, NR1I3, NR2B1 and NR2A1 were also associated with a significant decrease in blood counts from baseline. No haplotype was found to exert any effects on the pharmacodynamics parameters.
CONCLUSIONS: The present exploratory study identified several SNPs in the genes encoding regulatory nuclear receptors which may account for the interpatient variability in docetaxel pharmacokinetics and pharmacodynamics. These findings highlight the important role of regulatory nuclear receptors on the disposition of docetaxel.

Related:

Docetaxel

Nasopharyngeal Cancer

Liu Y, Song H, Pan J, Zhao J
Comprehensive gene expression analysis reveals multiple signal pathways associated with prostate cancer.
J Appl Genet. 2014; 55(1):117-24 [PubMed] Related Publications

Prostate cancer (PC) depends on androgenic signaling for growth and survival. To data, the exact molecular mechanism of hormone controlling proliferation and tumorigenesis in the PC remains unclear. Therefore, in this study, we explored the differentially expressed genes (DEGs) and identified featured genes related to hormone stimulus from PC. Two sets of gene expression data, including PC and normal control sample, were downloaded from Gene Expression Omnibus (GEO) database. The t-test was used to identify DEGs between PC and controls. Gene ontology (GO) functional annotation was applied to analyze the function of DEGs and screen hormone-related DEGs. Then these hormone-related DEGs were further analyzed in constructed cancer network and Human Protein Reference Database to screen important signaling pathways they participated in. A total of 912 DEGs were obtained which included 326 up-regulated genes and 586 down-regulated genes. GO functional enrichment analysis identified 50 hormone-related DEGs associated with PC. After pathway and PPI network analysis, we found these hormone-related DEGs participated in several important signaling pathways including TGF-β (TGFB2, TGFB3 and TGFBR2), MAPK (TGFB2, TGFB3 and TGFBR2), insulin (PIK3R3, SHC1 and EIF4EBP1), and p53 signaling pathways (CCND2 and CDKN1A). In addition, a total of five hormone-related DEGs (SHC1, CAV1, RXRA, CDKN1A and SRF) were located in the center of PPI network and 12 hormone-related DEGs formed six protein modules. These important signal pathways and hormone-related DEGs may provide potential therapeutic targets for PC.

Related:

Prostate Cancer