Biology subjects

Nonn, L.

Publications and source records attributed to Nonn, L..

6 recordsLinked to original sources

bioRxiv2026

Vitamin D deficiency alters prostate epithelial differentiation and increases prostate cancer aggressiveness in ex vivo and in vivo models

Here, we examined the consequences of biologically relevant vitamin D deficiency, a known risk factor for aggressive prostate cancer, using ex vivo and in vivo models. Phenotypic and single-cell RNA sequencing of mouse prostate organoids showed that vitamin D deficiency stunted luminal cell differentiation more than androgen deficiency, which is a known driver of prostate development. Mice fed a vitamin D-deficient diet showed significantly altered expression of androgen-responsive genes in their prostate luminal cells, as determined by single-cell RNA sequencing. MDA-PCa-2b human prostate cancer cells, when maintained for 6 months in 1,25-dihydroxyvitamin D, lost the ability to form xenografts, despite normal proliferation in vitro. RNA sequencing showed that these cells also had disruptions in androgen signaling and multiple cancer-related pathways. This study offers new insights and validation of vitamin Ds role in both benign and malignant prostate biology, underscoring its essential hormonal functions and supporting strategies for vitamin D supplementation to reduce prostate cancer risk in vulnerable populations. STATEMENT OF SIGNIFICANCEVitamin D is an essential hormone, however, the non-calcemic consequences of vitamin D deficiency remain poorly defined, despite its high prevalence in the population. This study demonstrates significant biological consequences of vitamin D deficiency on prostate cells at biologically relevant levels in multiple systems.

cancer biology↗

bioRxiv2023

Prostate-derived circulating microRNAs add prognostic value to prostate cancer risk calculators

Prostate cancer is the second leading cause of malignancy-related deaths among American men. Active surveillance is a safe option for many men with less aggressive disease, yet definitively determining low-risk cancer is challenging with biopsy alone. Herein, we sought to identify prostate-derived microRNAs in patient sera and serum extracellular vesicles, and determine if those microRNAs improve upon the current clinical risk calculators for prostate cancer prognosis before and after biopsy. Prostate-derived intracellular and extracellular vesicle-contained microRNAs were identified by small RNA sequencing of prostate cancer patient explants and primary cells. Abundant microRNAs were included in a custom microRNA PCR panel that was queried in whole serum and serum extracellular vesicles from a diverse cohort of men diagnosed with prostate cancer. The levels of these circulating microRNAs significantly differed between indolent and aggressive disease and improved the area under the curve for pretreatment nomograms of prostate cancer disease risk. The microRNAs within the extracellular vesicles had improved prognostic value compared to the microRNAs in the whole serum. In summary, quantifying microRNAs circulating in extracellular vesicles is a clinically feasible assay that may provide additional information for assessing prostate cancer risk stratification.

cancer biology↗

bioRxiv2022

Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

BackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined. ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients. ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.

cancer biology↗

bioRxiv2021

Vitamin D deficiency increases prostatic megalin expression and globulin-bound testosterone import, increasing prostatic androgens in African American men

Vitamin D deficiency is associated with an increased risk of prostate cancer (PCa) mortality and is hypothesized to contribute to PCa aggressiveness and disparities in African American populations. The prostate epithelium was recently shown to express megalin, an endocytic receptor that internalizes globulin-bound hormones, which suggests regulation of prostate hormone levels, in contrast to the free hormone hypothesis. Here, we demonstrated that megalin imports testosterone bound to sex hormone-binding globulin into prostate cells. Prostatic loss of Lrp2 (megalin) in a mouse model resulted in reduced prostate testosterone and dihydrotestosterone (DHT) levels. Megalin expression was regulated and suppressed by 25-hydroxyvitamin D (25D) in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants, indicating a negative feedback loop. In patent samples, the relationships between hormones support this feedback mechanism, as prostatic DHT levels are higher in African American men and are inversely correlated with serum 25D status. Megalin levels are reduced in localized PCa by the Gleason grade and in patients with future disease recurrence. Our findings suggest that the free hormone hypothesis should be revisited for testosterone and highlight the impact of vitamin D deficiency on prostate androgen levels, which are known drivers of PCa. Thus, we revealed a mechanistic link between vitamin D and PCa disparities observed in African Americans.

cancer biology↗

bioRxiv2020

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

Vitamin D is an essential steroid hormone that regulates systemic calcium homeostasis and cell fate decisions, including differentiation in many cell types. The prostate gland is hormonally regulated, requiring steroids for proliferation and terminal differentiation of secretory luminal cells. Vitamin D deficiency is associated with higher risk of lethal prostate cancer with an aggressive dedifferentiated pathology, linking vitamin D sufficiency to epithelial differentiation homeostasis. To determine regulation of prostate epithelial differentiation by vitamin D status, patient-derived benign prostate epithelial organoids were maintained in vitamin D deficient (vehicle) or sufficient (10 nM 1,25-dihydroxyvitamin D) conditions and assessed by phenotype and single cell RNA sequencing. Mechanistic validation demonstrated that vitamin D sufficiency promoted organoid growth and accelerated differentiation of lineage-committed cells by inhibiting canonical Wnt activity and Wnt family member DKK3. Wnt dysregulation is a known contributor to aggressive prostate cancer, thus these findings further link vitamin D deficiency to lethal disease.

cell biology↗

bioRxiv2018

Cell-type specific expression of oncogenic and tumor suppressive microRNAs in the human prostate and prostate cancer

MiR-1 and miR-143 are frequently reduced in human prostate cancer (PCa), while miR-141 and miR-21 are frequently elevated. Consequently, these miRNAs have been studied as cell-autonomous tumor suppressors and oncogenes. However, the cell-type specificity of these miRNAs is not well defined in prostate tissue. Through two different microdissection techniques, and droplet digital RT-PCR, we quantified these miRNAs in the stroma and epithelium of radical prostatectomy specimens. In contrast to their purported roles as cell-autonomous tumor suppressors, we found miR-1 and miR-143 expression to be predominantly stromal. Conversely, miR-141 was predominantly epithelial. MiR-21 was detected in both stroma and epithelium. Strikingly, the levels of miR-1 and miR-143 were significantly reduced in tumor-associated stroma, but not tumor epithelium. Gene expression analyses in human cell lines, tissues, and prostate-derived stromal cultures support the cell-type selective expression of miR-1, miR-141, and miR-143. Analyses of the PCa Genome Atlas (TCGA-PRAD) showed a strong positive correlation between stromal markers and miR-1 and miR-143, and a strong negative correlation between stromal markers and miR-141. In these tumors, loss of miR-1 and gain of miR-21 was highly associated with biochemical recurrence. These data shed new light on stromal and epithelial miRNA expression in the PCa tumor microenvironment.

cancer biology↗