Genome-wide identification of target genes to vitamin D and analysis of the molecular mechanisms underlying its therapeutic properties
Bibliographic record
Abstract
1,25-dihydroxyvitamin D3 (1,25D3), also know as cholecalciferol, is still best known as a regulator of calcium homeostasis. However more recent studies have revealed the pleiotropic actions of 1,25D 3, including immune and nervous system modulation, and cellular proliferation and differentiation. Epidemiological and model studies have revealed the anticancer properties of 1,25D3, which modulates gene transcription through the nuclear vitamin D receptor (VDR). This dissertation is composed of four different studies that focus on the molecular and genetic events that underlie the anticancer properties of 1,25D3. Our first set of experiments was a genome-wide exploration of cognate 1,25D3 response elements (VDREs), described as direct or everted repeats of PuG(G/T)TCA motifs separated by 3 or 6 bp at the promoters of 1,25D3 target genes that are recognized by the VDR. Our study identified over 3000 conserved VDREs and 158 human elements regulated in oral cancer cells. Expanding on this study, we then provided both molecular and genomic evidence that 1,25D3 and retinoic acid, another cancer preventive agent, can signal through a newly characterized common response element. This response element is an everted repeat of the consensus PuG(G/T)TCA motif separated by 8 bp (ER8). We characterized the ER8 element on the cyclin-dependent kinase inhibitor p19ink4d gene and provided evidence that induction of this gene through the ER8 element by either ligand mediates cell cycle arrest and prevents autophagy by 1,25D3. Furthermore, well-differentiated squamous carcinoma cells (SCC) are sensitive to 1,25D3, whereas poorly differentiated SCC cells are partially resistant. This brought about the investigation of the effects of 1,25D3 combined with histone deacetylase (HDAC) inhibitor TSA on 1,25D3-resistant SCC4 oral cancer cells. We found that SCC4 cells were highly sensitive to this combination, which induced G 2/M arrest and mitotic catastrophe. Finally, since single compound therapy is more advantageous from the pharmacotherapeutic point of view than multiple compound therapy, we created triciferol, a hybrid molecule which combines 1,25D3 agonism and HDAC inhibition. Triciferol behaves like both 1,25D3 and TSA as it activates 1,25D3 target genes with similar potency to 1,25D3, acetylates histones and induces G 2/M arrest and both mitotic catastrophe and autophagy in cancer cells. The work presented in this dissertation contains multiple original contributions to the 1,25D3 field as it provides: (i) insights on the direct target genes underlying the physiological actions of 1,25D3; (ii) evidence for cross-talk between 1,25D3 and RA, while uncovering the role of p194D in cell survival; (iii) support for the notion of 1,25D 3 insufficiency in the population may reduce the efficacy of HDACi chemotherapy; and a demonstration of the feasibility of combining HDAC inhibition with VDR agonism in 1,25D3 analogues to enhance their therapeutic potential.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".