Bibliographic record
Abstract
Background: EZH2 is a histone methyltransferase (HKMT) responsible for the maintenance of epigenetic silencing of genes through maintenance of the repressive H3K27me3 mark and it is aberrantly regulated in numerous cancers, including breast cancer where it is linked to aggressive phenotypes and poor clinical outcomes. EHMT2 is a related HKMT responsible for gene silencing by mediating H3K9me3 levels. EHMT2 is also responsible for H3K27me1 and has been shown to physically interact with EZH2. Specific inhibitors of EZH2 are available and have been shown to be effective in cancers with EZH2 mutation driven phenotypes (e.g. follicular lymphoma) but have shown limited efficacy in epithelial cancers. Here we present the characterisation of novel dual HKMT inhibitors targeting both EZH2 and EHMT2, which we believe will have a greater impact than individual inhibitors in reversing EZH2 mediated silencing. Results: Utilising publicly available data, we show expression of EZH2 and related subunits of the PRC2 complex and related EHMT2/EHMT1 complex range greatly in normal tissue, but EZH2 and EHMT2 expression are consistently up-regulated in numerous cancers. We show that CNV and mutation of EZH2 and EHMT2 infrequently occur in breast cancer- however, in breast cancer high expression of EZH2 is linked to reduced RFS and OS of patients. In breast cancer cell lines, dual HKMT inhibitors up-regulate EZH2 target genes, in gene specific and genome wide manner, to a greater degree than EZH2 or EHMT2 inhibition alone and induce expression of genes associated with apoptotic pathways. This up-regulation of silenced genes occurs concurrently with a decrease in H3K27me3 and H3K9me3 levels on target genes. In breast cancer cells and ovarian cancer cells, dual HKMT inhibitors reduce cell clonogenicity, cancer stem cell activity, cancer stem cell self-renewal capacity, and sensitise cancer stem cells to Paclitaxel and Cisplatin treatment. Conclusions: Novel dual inhibitors of EZH2 and EHMT2 alter gene expression and inhibit cell growth and cancer stem cell activity in wild-type EZH2 tumour cells. These data support the further preclinical and clinical evaluation of such inhibitors in triple negative breast cancer and epithelial ovarian cancer.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".