The impact of vitamin D on cancer: A mini review.

In this review, we summarize the most recent advances in vitamin D cancer research to provide molecular clarity, as well as its translational trajectory across the cancer landscape. Vitamin D is well known for its role in regulating mineral homeostasis; however, vitamin D deficiency has also been linked to the development and progression of a number of cancer types. Recent epigenomic, transcriptomic, and proteomic studies have revealed novel vitamin D-mediated biological mechanisms that regulate cancer cell self-renewal, differentiation, proliferation, transformation, and death. Tumor microenvironmental studies have also revealed dynamic relationships between the immune system and vitamin D\u27s anti-neoplastic properties. These findings help to explain the large number of population-based studies that show clinicopathological correlations between circulating vitamin D levels and risk of cancer development and death. The majority of evidence suggests that low circulating vitamin D levels are associated with an increased risk of cancers, whereas supplementation alone or in combination with other chemo/immunotherapeutic drugs may improve clinical outcomes even further. These promising results still necessitate further research and development into novel approaches that target vitamin D signaling and metabolic systems to improve cancer outcomes

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition.

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti- cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand- bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR’s integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients

GDNF promotes hair formation and cutaneous wound healing by targeting bulge stem cells.

Glial-cell-derived neurotrophic factor (GDNF) is a well-studied neuroregenerative factor; however, the degree to which it supports hair formation and skin wound repair is not known. By using a Gfra1 (GDNF family receptor alpha 1) knock-in reporter mouse line, GDNF signaling was found to occur within hair bulge stem cells (BSCs) during the initiation of the hair cycle and early stages of hair formation after depilation. Both recombinant and transgene overexpression of GDNF promoted BSC colony growth, hair formation, and skin repair after wounding through enhanced self-renewal of BSCs and commitment of BSC-derived progenitors into becoming epidermal cells at the injury site. Conditional ablation of Gfra1 among BSCs impaired the onset of the hair cycle, while conditional ablation of the GDNF family member signal transducer, Ret, within BSCs prevented the onset of the hair cycle and depilation-induced anagen development of hair follicles. Our findings reveal that GDNF promotes hair formation and wound repair and that bulge stem cells are critical mediators of both

The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts

Heterogeneous nuclear ribonucleoprotein (hnRNP) C plays a key role in RNA processing but also exerts a dominant negative effect on responses to 1,25-dihydroxyvitamin D (1,25(OH)(2)D) by functioning as a vitamin D response element-binding protein (VDRE-BP). hnRNPC acts a tetramer of hnRNPC1 (huC1) and hnRNPC2 (huC2), and organization of these subunits is critical to in vivo nucleic acid-binding. Overexpression of either huC1 or huC2 in human osteoblasts is sufficient to confer VDRE-BP suppression of 1,25(OH)(2)D-mediated transcription. However, huC1 or huC2 alone did not suppress 1,25(OH)(2)D-induced transcription in mouse osteoblastic cells. By contrast, overexpression of huC1 and huC2 in combination or transfection with a bone-specific polycistronic vector using a “self-cleaving” 2A peptide to co-express huC1/C2 suppressed 1,25D-mediated induction of osteoblast target gene expression. Structural diversity of hnRNPC between human/NWPs and mouse/rat/rabbit/dog was investigated by analysis of sequence variations within the hnRNP CLZ domain. The predicted loss of distal helical function in hnRNPC from lower species provides an explanation for the altered interaction between huC1/C2 and their mouse counterparts. These data provide new evidence of a role for hnRNPC1/C2 in 1,25(OH)(2)D-driven gene expression, and further suggest that species-specific tetramerization is a crucial determinant of its actions as a regulator of VDR-directed transactivation

Vitamin D Modulation of Mitochondrial Oxidative Metabolism and mTOR Enforces Stress Adaptations and Anticancer Responses

The relationship between the active form of vitamin D3 (1,25-dihydroxyvitamin D, 1,25(OH)2D) and reactive oxygen species (ROS), two integral signaling molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)2D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)-sensitive MG-63 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)2D decreased mt ROS levels, membrane potential (ΔΨmt), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress adaptive responses. Using a mitochondria-focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)2D lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)2D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non-oxidative energy metabolism. ATACseq revealed putative oxi-sensitive and tumor-suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG-63 cells yet sequestered in the cytoplasm after 1,25(OH)2D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)2D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.</p

The acyl-CoA Synthetase, pudgy, Promotes Sleep and Is Required for the Homeostatic Response to Sleep Deprivation

The regulation of sleep and the response to sleep deprivation rely on multiple biochemical pathways. A critical connection is the link between sleep and metabolism. Metabolic changes can disrupt sleep, and conversely decreased sleep can alter the metabolic environment. There is building evidence that lipid metabolism, in particular, is a critical part of mounting the homeostatic response to sleep deprivation. We have evaluated an acyl-CoA synthetase, pudgy (pdgy), for its role in sleep and response to sleep deprivation. When pdgy transcript levels are decreased through transposable element disruption of the gene, mutant flies showed lower total sleep times and increased sleep fragmentation at night compared to genetic controls. Consistent with disrupted sleep, mutant flies had a decreased lifespan compared to controls. pdgy disrupted fatty acid handling as pdgy mutants showed increased sensitivity to starvation and exhibited lower fat stores. Moreover, the response to sleep deprivation is reduced when compared to a control flies. When we decreased the transcript levels for pdgy using RNAi, the response to sleep deprivation was decreased compared to background controls. In addition, when the pdgy transcription is rescued throughout the fly, the response to sleep deprivation is restored. These data demonstrate that the regulation and function of acyl-CoA synthetase plays a critical role in regulating sleep and the response to sleep deprivation. Endocrine and metabolic signals that alter transcript levels of pdgy impact sleep regulation or interfere with the homeostatic response to sleep deprivation

WISE/NEOWISE observations of Active Bodies in the Main Belt

We report results based on mid-infrared photometry of 5 active main belt objects (AMBOs) detected by the Wide-field Infrared Survey Explorer (WISE) spacecraft. Four of these bodies, P/2010 R2 (La Sagra), 133P/Elst-Pizarro, (596) Scheila, and 176P/LINEAR, showed no signs of activity at the time of the observations, allowing the WISE detections to place firm constraints on their diameters and albedos. Geometric albedos were in the range of a few percent, and on the order of other measured comet nuclei. P/2010 A2 was observed on April 2-3, 2010, three months after its peak activity. Photometry of the coma at 12 and 22 {\mu}m combined with ground-based visible-wavelength measurements provides constraints on the dust particle mass distribution (PMD), dlogn/dlogm, yielding power-law slope values of {\alpha} = -0.5 +/- 0.1. This PMD is considerably more shallow than that found for other comets, in particular inbound particle fluence during the Stardust encounter of comet 81P/Wild 2. It is similar to the PMD seen for 9P/Tempel 1 in the immediate aftermath of the Deep Impact experiment. Upper limits for CO2 & CO production are also provided for each AMBO and compared with revised production numbers for WISE observations of 103P/Hartley 2.Comment: 32 Pages, including 5 Figure

Implications of the Small Spin Changes Measured for Large Jupiter-Family Comet Nuclei

Rotational spin-up due to outgassing of comet nuclei has been identified as a possible mechanism for considerable mass-loss and splitting. We report a search for spin changes for three large Jupiter-family comets (JFCs): 14P/Wolf, 143P/Kowal-Mrkos, and 162P/Siding Spring. None of the three comets has detectable period changes, and we set conservative upper limits of 4.2 (14P), 6.6 (143P) and 25 (162P) minutes per orbit. Comparing these results with all eight other JFCs with measured rotational changes, we deduce that none of the observed large JFCs experiences significant spin changes. This suggests that large comet nuclei are less likely to undergo rotationally-driven splitting, and therefore more likely to survive more perihelion passages than smaller nuclei. We find supporting evidence for this hypothesis in the cumulative size distributions of JFCs and dormant comets, as well as in recent numerical studies of cometary orbital dynamics. We added 143P to the sample of 13 other JFCs with known albedos and phase-function slopes. This sample shows a possible correlation of increasing phase-function slopes for larger geometric albedos. Partly based on findings from recent space missions to JFCs, we hypothesise that this correlation corresponds to an evolutionary trend for JFCs. We propose that newly activated JFCs have larger albedos and steeper phase functions, which gradually decrease due to sublimation-driven erosion. If confirmed, this could be used to analyse surface erosion from ground and to distinguish between dormant comets and asteroids