In line with the established points that changes in the global genome-wide landscape of histone methylation are essential for cancer cell proliferation and stem-like traits during cancer onset and progression, we demonstrated the utility of TOX3/WDR5/H3K4me3 signaling axis as selective chromatin binders in CRC cells to promote cCSCs expansion and drug resistance by stably expressing ABCG2. The gene discussed is TOX3; the disease is cancer.