DNA Demethylase transforms normal cells into highly invasive and metastatic cancer cells: Identification and characterization of novel metastatic cancer targets, therapeutic intervention for these targets, and signaling pathways leading to DNA demethylation
Bibliographic record
Abstract
13 Introduction: Cancer cells are hallmarked by global DNA hypomethylation. MBD2 is the only protein that has been implicated in removal of methyl groups from CG di-nucleotides. Inhibition of MBD2 attenuates tumorigenesis, metastasis, and reverses the hypomethylation of metastatic genes. Additionally, germ line deletion of the mbd2 gene protects mice from intestinal tumors; therefore, we tested the hypothesis that oncogenic signals induce MBD2 resulting in metastatic transformation of cells through the triggering of global DNA hypomethylation resulting in metastatic gene activation. Results: Ectopic MBD2 expression but not mutant MBD2 causes global genomic demethylation in normal (NIH 3T3, MCF10A, Primary Human Fibroblasts, and Primary Hepatocytes) and transformed (MCF7, HA-RAS-NIH3T3, and T24) cell lines. MBD2 knockdown in these cell lines results in increased DNA methylation supporting the hypothesis that MBD2 is involved in global hypomethylation. Furthermore, cell lines with increased MBD2 have greater in-vitro demethylase activity. Ectopic MBD2 causes normal cells to become highly transformed and invasive and increases the invasiveness of transformed cell lines. MBD2 overexpressing cells are tumorgenic in NUDE mice and invade and degrade the bone of SCID mice. We show that MBD2 causes this by binding to and demethylating the gene promoters of cell type specific gene sets. We have identified several metastatic promoting genes like MerTK as well as novel metastatic genes that are regulated by MBD2 promoted demethylation. We have proven that these genes are required for metastasis using siRNA strategies in transformed cell lines and developed a therapeutic intervention strategy against a novel metastatic target. Finally, we show that MBD2 is induced by activated HA-RAS, regulates demethylation and metastatic gene activation in these cells, and is regulated by HA-RAS associated transcription factors. Summary: Our results have unraveled a critical transformation pathway leading from RAS through MBD2 to global hypomethylation and activation of metastatic genes as well. These data support a new therapeutic approach to metastasis, which would involve targeting MBD2 and DNA demethylation. Supported by a grant from the National Cancer Institute of Canada to MS.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".