Fig. 7.

KMT2B and KMT2D KD promote tertiary metastasis to the brain. A MDA-MB-231 BCCs (5 × 10⁵) with scramble sequence-GFP, KMT2B KD-GFP, and KMT2D KD-GFP were injected intravenously into nude female mice as for Fig. 6. On day 7, the brain was harvested, and the paraffin-embedded slides were imaged to assess for BCCs (green) and for Ki67 cells (teal cells: green/BCCs + blue/Ki67). Image magnification: 100x. B and C The total number of BCCs for three mice treated with vehicle were counted in 10 fields per section. The data are presented as the mean ± SD total number of viable cells in brains of mice injected with KMT2B (B) or KMT2D (C) KD, or scramble shRNA. D and E Percent cell death after carboplatin treatment was calculated with the total number of BCCs for vehicle set as 100% viablity. The data for KMT2B (D) and KMT2D (E) are calculated as the mean ± SD. F DNA methylation and oxidation cycle: Genomic DNA is methylated (5mC) by DNA methyltransferase enzymes (DNMTs). TET enzymes (TET1, TET2, TET3) can successively oxidize 5mC into 5hmC, 5fC and 5caC. Subsequently, 5fC and 5caC can be excised by TDG and further repair by the Base Excision Repair (BER) system leading to DNA de-methylation. G Shown is a overall summary of the findings. The cartoon indicates a cell-autonmous role for H3K4 with the data supporting potential drug target. The outcome on DNA methylation has not proved to be cell autonomous. The data however suggested the inclusion in a biomarker panel and follow-up treatment