Vitamin D enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk.

Background: Vitamin D (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin-based chemotherapy, however 30%-50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown.

Transcriptional changes associated with growth of muscle-invasive bladder cancer cell lines in nude mice.

Cancer cells set in motion transcriptomic programs allowing for adaptation and growth in immunocompromised mice to form xenografts, a frequently used tool in cancer research. 2D cultures may not be representative of tumors growing in a complex host microenvironment. This can result in different responses to the same agent tested and which impedes the process of developing novel therapeutics.

Calcium, magnesium, and whole-milk intakes and high-aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project (PCaP).

Background: Calcium and dairy product intakes have been positively associated with prostate cancer risk. An imbalance in concentrations of calcium and magnesium has been associated with multiple chronic diseases, although few studies have examined the relation with prostate cancer aggressiveness.

Objective: The goal of this study was to examine the association between dietary intakes of calcium and magnesium, the calcium-to-magnesium ratio (Ca:Mg), and dairy products and prostate cancer aggressiveness.

The role of STAG2 in bladder cancer.

Stromal Antigen 2 (STAG2) is one of four components of the cohesin complex and predominantly functions in sister chromatid cohesion and segregation. STAG2 is the most frequently mutated cohesin subunit and was recently identified as a gene that is commonly altered in bladder cancer. The significance of these mutations remains controversial.

Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis.

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma).

Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer.

Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation.

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function Mutations.

African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing ( = 102) and targeted validation ( = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in , an ETS transcriptional repressor, in 5% of cases.

Heme oxygenase-1 in the forefront of a multi-molecular network that governs cell-cell contacts and filopodia-induced zippering in prostate cancer.

Prostate cancer (PCa) cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown that heme oxygenase 1 (HO-1) is implicated in cell morphology regulation in PCa. Here, through a multi 'omics' approach we define the HO-1 interactome in PCa, identifying HO-1 molecular partners associated with the integrity of the cellular cytoskeleton.

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts.

Purpose: Effective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response.

Experimental Design: We performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX).

Association between Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP.

Background: African Americans (AAs) have lower circulating 25-hydroxyvitamin D3 [25(OH)D3] concentrations and higher prostate cancer (CaP) aggressiveness than other racial/ethnic groups. The purpose of the current study was to examine the relationship between plasma 25(OH)D3, African ancestry and CaP aggressiveness among AAs and European Americans (EAs).

Methods: Plasma 25(OH)D3 was measured using LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in 537 AA and 663 EA newly-diagnosed CaP patients from the North Carolina-Louisiana Prostate Cancer Project (PCaP) classified as having either 'high' or 'low' aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis.

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer.

Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.

6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer.

Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). In a comparative fashion much less is known about copy number alterations in TCC-UB, but it appears that amplification of chromosome 6p22 is one of the most frequent changes. Using fluorescence in situ hybridization (FISH) analyses, we evaluated chromosomal 6p22 amplification in a large cohort of bladder cancer patients with complete surgical staging and outcome data.

Vitamin D and cancer: clinical aspects.

There are substantial preclinical and epidemiologic data that suggest that vitamin D plays a role in the prevention and treatment of cancer. Numerous observational studies have shown that low blood levels of 25(OH) vitamin D (cholecalciferol), estimated by geographical location, diet and activity assessment or measured serum levels are associated with a higher risk of cancer and worse cancer-specific survival as well as numerous morbidities to e.g.

Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: association with the BORIS/CTCF expression ratio and advanced stage.

Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined.

Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples.

BORIS/CTCFL expression is insufficient for cancer-germline antigen gene expression and DNA hypomethylation in ovarian cell lines.

Expression of the cancer-germline (CG) (or cancer-testis) antigen gene BORIS/CTCFL has been proposed to mediate activation of CG antigen genes in cancer. Consistent with this idea, we have observed that BORIS is frequently expressed in ovarian cancer, often in conjunction with other CG genes. Here we assessed the role of BORIS in CG antigen gene regulation and DNA methylation using normal and cancerous ovarian cell lines, and the CG genes MAGE-A1, NY-ESO-1, and XAGE-1 as models.

Distinct roles for histone methyltransferases G9a and GLP in cancer germ-line antigen gene regulation in human cancer cells and murine embryonic stem cells.

The H3K9me2 histone methyltransferases G9a and GLP repress Mage-a class cancer germ-line (CG) antigen gene expression in murine embryonic stem (ES) cells, but the role of these enzymes in CG antigen gene regulation in human cancer cells is unknown. Here we show that whereas independent or dual knockdown of G9a and GLP in human cancer cells leads to reduced global and CG antigen promoter-associated H3K9me2 levels, it does not activate CG antigen gene expression. Moreover, CG antigen gene repression is maintained following pharmacologic targeting of G9a or treatment of G9a knockdown cells with the histone deacetylase inhibitor trichostatin A.

Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer.

Purpose: The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC.

Experimental Design: We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR.

DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer.

Brother of the Regulator of Imprinted Sites (BORIS/CTCFL) is an autosomal cancer germline (CG) or cancer-testis antigen gene and paralog of CTCF that has been proposed to function as an oncogene in human cancer via dysregulation of the cancer epigenome. Here we show that genetic disruption of DNA methylation in human cancer cells induces BORIS expression, coincident with DNA hypomethylation and an altered histone H3 modification pattern at the BORIS promoter. Rapid amplification of cDNA ends (RACE) mapping revealed that the transcriptional start site of BORIS in human testis, DNMT deficient human cancer cells, and human epithelial ovarian cancer (EOC) tissues, is similar and lies within the 5' CpG island.

An improved synthesis of psammaplin A.

The marine natural product, psammaplin A, was first isolated from the Psammaplinaplysilla sponge in 1987. Since that time, psammaplin A has shown a wide spectrum of biological activities that include enzyme inhibitory activities resulting in antibacterial and antitumor effects. An improved synthesis of psammaplin A has been developed, making the compound more easily accessible for further biological evaluations.

Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells.

We have reported previously that protein kinase C (PKC) signaling can mediate a program of cell cycle withdrawal in IEC-18 nontransformed intestinal crypt cells, involving rapid disappearance of cyclin D1, increased expression of Cip/Kip cyclin-dependent kinase inhibitors, and activation of the growth suppressor function of pocket proteins. In the current study, we present evidence to support a requisite role for PKC alpha in mediating these effects. Furthermore, analysis of the signaling events linking PKC/PKC alpha activation to changes in the cell cycle regulatory machinery implicate the Ras/Raf/MEK/ERK cascade.